Phenylethanolaminomethyltetralins and pharmaceutical use

ABSTRACT

New phenylethanolaminomethyltetralins of formula (I) ##STR1## wherein E represents hydrogen, (C 1  -C 4 )alkyl, (C 1  -C 4 )alkoxy, phenyl, nitro, halogen, or trifluoromethyl, 
     L represents hydrogen, (C 1  -C 4 )alkyl, (C 1  -C 4 )alkyoxy, phenyl, nitro, or halogen, or 
     E and L taken together represent a group --CH═CH--CH═CH-- or --CH 2  --CH 2  --CH 2  --CH 2  --, and 
     G represents hydrogen, chloro, hydroxy or an --OG&#39; group wherein G&#39; represents a (C 1  -C 4  (alkyl group either unsubstituted or substituted with hydroxy, (C 1  -C 4 )alkoxy, (C 1  -C 4 )alkoxycarbonyl, carboxy, or (C 3  -C 7 )cycloalkyl; a (C 3  -C 7 )cycloalkyl group; or a (C 2  -C 4 )alkanoyl group; and salts thereof, are described which showed to be active as intestinal motility modulating agents and intraocular hypertension lowering agents. 
     Also described is a process for the preparation of the new compounds and the intermediates of formula (III) ##STR2## employed in said process.

The present invention relates to new phenylethanolaminomethyltetralins,a process for the preparation thereof, the intermediates in said processand the pharmaceutical compositions containing saidphenylethanolaminomethyltetralins as the active principles.

European Patent 211,721 describes phenylethanolaminotetralinssubstituted on the aromatic ring of the tetralin moiety of followingformula (A): ##STR3## wherein X represents hydrogen, halogen,trifluoromethyl, or lower alkyl and R represents hydrogen, unsubstitutedmethyl or methyl substituted with carboxy or alkoxycarbonyl, endowedwith very interesting pharmacological properties. Compounds (A) areindicated inter alia as intestinal and uterine motility modulators.

It has now been found that compounds which differ from the compoundsknown essentially in the presence of a methylene group (--CH₂ --)between the tetralin moiety and the amino group, have an intestinalmotility modulating activity higher than or at least equal to theactivity of the corresponding known phenylethanolaminotetralins,associated with a higher selectivity towards the intestine.

In one of its embodiments, therefore the present invention concernsphenylethanolaminomethyltetralins of following formula (I) : ##STR4##wherein E represents hydrogen, (C₁ -C₄)alkyl, (C₁ -C₄)alkoxy, phenyl,nitro, halogen, or trifluoromethyl,

L represents hydrogen, (C₁ -C₄)alkyl, (C₁ -C₄)alkoxy, phenyl, nitro, orhalogen, or

E and L taken together represent a group --CH═CH--CH═CH-- or --CH₂ --CH₂--CH₂ --CH₂ --, and

G represents hydrogen, chloro, hydroxy or an --OG' group wherein G'represents a (C₁ -C₄)alkyl group either unsubstituted or substitutedwith hydroxy, (C₁ -C₄)alkoxy, (C₁ -C₄)alkoxycarbonyl, carboxy, or (C₃-C₇)cycloalkyl; a (C₃ -C₇)cycloalkyl group; or a (C₂ -C₄)alkanoyl group;and their salts.

As used herein

the term "(C₁ -C₄)alkyl" designates a monovalent radical of a saturated,straight or branched hydrocarbon which may contain from 1 to 4 carbonatoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl ortert-butyl;

the term "(C₁ -C₄)alkoxy" designates a straight or branched alkoxyradical of from 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy,isopropoxy, n-butoxy, sec-butoxy, or tert-butoxy;

the term "(C₃ -C₇ -cycloalkyl" identifies a monovalent radical of asaturated cyclic hydrocarbon of from 3 to 7 carbon atoms, such ascyclopropyl, cyclobutyl, cyclopentyl, cyclopentyl substituted with oneor two methyl groups or with an ethyl group, or cyclohexyl,methyl-cyclohexyl, or cycloheptyl;

the term "(C₂ -C₄)alkanoyl" designates an acyl radical deriving from analiphatic saturated carboxylic acid containing from 2 to 4 carbon atoms,i.e. acetyl, propionyl, 2-methylpropionyl, and butyryl;

the term "halogen" includes the four forms thereof fluoro, chloro,bromo, and iodo, the former three being preferred;

the terms "tetralin" and "tetralone" actually refers to the1,2,3,4-tetrahydronaphthalene ring.

The term "salts" of the compounds of formula (I) according to thepresent invention, includes the addition salts with pharmaceuticallyacceptable mineral or organic acids such as the hydrochloride,hydrobromide, sulfate, hydrogensulfate, dihydrogenphosphate, citrate,maleate, tartrate, fumarate, gluconate, methanesulfonate,2-naphthalenesulfonate, and the like, as well as the addition saltswhich allow an easy separation or crystallisation of the compounds offormula (I), such as the picrate and the oxalate, or the addition saltswith optically active acids, such as camphorsulfonic acids, mandelic orsubstituted mandelic acids.

Moreover, when the compounds of formula (I) contain a free carboxygroup, the term "salts" also includes the salts thereof with mineralbases, preferably those with alkali metals such as sodium or potassium,or with organic bases, such as trometamol.

In the above formula (I), the two asymmetric carbons are marked by anasterisk. All the compounds of formula (I) may therefore exist as fourdifferent stereoisomers (R,R), (R,S), (S,R), and (S,S). The opticallypure isomers, as well as the mixtures of two, three or all the fourisomers, in any proportion, are part of the present invention. Otherasymmetric centres might be present in the E, L and G groups.Analogously, the stereoisomers deriving from the presence of saidadditional chiral centres and their mixtures are part of the presentinvention.

For the expression of the pharmacological activity, the preferredconfiguration of the chiral carbon of the ethanolamino moiety is anywaythe (R) absolute configuration. The class of compounds of formula (I)wherein E, L, and G are as defined above and the chiral carbon of theethanolamino chain has the (R) absolute configuration representstherefore a preferred embodiment of the invention.

A preferred group of compounds of the present invention comprises thosecompounds of formula (I) wherein E and L are as defined above and Grepresents hydrogen, hydroxy or an --OG' group wherein G' represents (C₁-C₄)alkyl either unsubstituted or substituted with hydroxy, (C₁-C₄)alkoxy, carboxy, (C₁ -C₄)alkoxycarbonyl, or (C₃ -C₇)cycloalkyl, andtheir salts.

Particularly preferred compounds of the present invention are thosecompounds of formula (I) wherein E is hydrogen, (C₁ -C₄)alkyl orhalogen, L is hydrogen and G represents hydrogen, hydroxy or an --OG'group wherein G' represents unsubstituted (C₁ -C₄)alkyl or (C₁ -C₄)alkylsubstituted with carboxy or (C₁ -C₄) alkoxycarbonyl, and their salts.

The compounds of formula (I) may be prepared by treating a compound offormula (II) ##STR5## wherein E and L are as defined above and theradical --W represents one of the following groups: ##STR6## whereinHalo stands for chloro, bromo, or iodo, and Y is a --COOH group or afunctional derivative thereof; with a compound of formula (III) ##STR7##wherein G is as defined above, and, when --W is different from ##STR8##treating the thus obtained product with a suitably selected reducingagent.

More particularly, the reaction between the compounds of formula (II)and the 2-aminomethyltetralin derivative of formula (III) is carried outunder different reaction conditions which essentially depend on thenature of the starting compound of formula (II) and mainly on themeaning of --W.

Said operative techniques, which are described in details hereinbelow,have been designated as Methods (a) to (d).

Method (a)

According to said method, opening of the epoxide of formula (IIa)##STR9## by the amine of formula (III) is carried out in an organicsolvent such as a lower alkanol, e.g. methanol, ethanol, andisopropanol, a cyclic or linear ether, or an amide such asdimethylformamide or dimethylacetamide, using an at least equimolaramount of the two reactants but preferably an excess of the amine offormula (III). The reaction temperature is typically comprised betweenroom temperature and the reflux temperature of the selected solvent. Abasic agent, such as triethylamine, sodium hydroxide or sodium acetate,may conveniently be employed.

Method (b)

In the reaction which involves condensation of the phenylglyoxal offormula (IIb) ##STR10## with the amine of formula (III) and reduction ofthe obtained product, the preferred operating conditions involvecarrying out the two reactions simultaneously, by contacting thecompound of formula (IIb) with that of formula (III) in the presence ofa suitably selected reducing agent. If the amine of formula (III) andthe phenylglyoxal of formula (IIb) do not contain groups which aresusceptible to reduction conditions, the reaction may be carried out bycatalytic hydrogenation in the presence, for instance, of platinumdioxide or Raney nickel, and of an alcoholic solvent, such as methanolor ethanol, at the atmospheric pressure or under pressure. According toalternative operating conditions, an alkali metal hydride such as sodiumborohydride, may be used, in the presence of an alcoholic solvent, suchas ethanol, preferably at low temperatures.

Method (c)

According to another method, the compounds of formula (I) are preparedby reacting the amine of formula (III) with an α-halo-acetophenone offormula (IIc) ##STR11## in an inert solvent, such as a linear or cyclicether, a lower alkanol, such as methanol, ethanol, or isopropanol, anaromatic hydrocarbon such as toluene, or benzene, a halogenatedaliphatic hydrocarbon such as chloroform, or a nitrile, such asacetonitrile.

This nucleophilic substitution is advantageously carried out at roomtemperature of in the cold. Reduction of the thus obtained product maybe achieved according to known techniques such as for instance bycatalytic hydrogenation in the presence of e.g. palladium on carbon,Raney nickel, or platinum dioxide, in an alcoholic solvent, such asmethanol or ethanol, preferably at low temperatures; or by the additionof lithium aluminum hydride in ethyl ether or in tetrahydrofuran, or, bythe action of an aluminum alkoxide, such as aluminum isopropoxide, in asolvent such as isopropanol, preferably at the reflux temperature, oralso by the action of NaCNBH₃ at a pH of about 5.

Method (d)

According to an alternative operating method, which represents apreferred embodiment of the present invention, the amine of formula(III) is reacted with a compound of formula (IId) ##STR12## wherein E,L, and Y are as defined above.

As carboxy functional derivatives, there may be employed acyl chlorides,anhydrides, mixed anhydrides, active esters or suitably activated freeacids, for instance by means of dicyclohexylcarbodiimide (DCCI) orbenzotriazolyl-N-oxytris-(dimethylamino)phosphonium hexafluorophosphate(BOP). The reaction between the compound of formula (IId) above and theaminomethyltetralin (III) is carried out in an aprotic, non-polar or,preferably, polar, organic solvent, such as dimethylformamide,dimethylsulfoxide, methylene chloride, benzene, and toluene, optionallyin the presence of a proton acceptor, such as an aliphatic tertiaryamine, e.g. triethylamine.

The thus obtained mandelamide of formula (IV) ##STR13## may be submitteddirectly to reduction of the amido group to methyleneamino.

The reduction step is carried out, for instance, by the action of ahydride, such as lithium aluminum hydride, or of a diborane,particularly of a reactant generating the diborane such as the complexbetween borane and dimethylsulfide, hereinafter designated as"borane-methyl sulfide". The reaction is carried out in an organicsolvent such as tetrahydrofuran, and the thus obtained compound offormula (I) is isolated according to conventional techniques. When amandelamide of formula (IV) is reduced wherein G is an --OG' group,wherein G' represents alkyl substituted with an optionally salifiedcarboxy group or with a (C₁ -C₄)alkoxycarbonyl group, selectivereduction of the amido group may be achieved by using borane-methylsulfide and carrying out the reaction at low temperatures (10°-25° C.).

When the desired product of formula (I) contains one or more groupswhich are susceptible to reduction conditions, it is generally preferredto use, as the starting material (II), a compound of formula (IIa) or tosuitably select, among those known in the literature, particularreducing agents and/or conditions which selectively or at leastpreferably, afford reduction of the chain between the amino group andthe benzene cycle, with formation of the desired --CH(OH)--CH₂ --NH--chain without altering the other groups.

Another general method for the preparation of the compounds of formula(I) wherein G is an --OG' group, involves conversion of the compounds(I) wherein G is a hydroxy group, prepared by any of the above methods,into the desired products by conventional O-alkylation or O-acylation byreaction of a compound of formula (I) wherein G is a hydroxy group withan alkylating or acylating agent of formula D--G' wherein G' is asdefined above and D represents a good leaving group.

This method is mostly preferred when G is an --OG' group wherein G'represents (C₁ -C₄)alkyl substituted with carboxy or (C₁-C₄)alkoxycarbonyl, or (C₂ -C₄)alcanoyl.

For example, O-alkylation may be carried out with optionally substituted(C₁ -C₄)alkyl halides, i.e. chlorides, iodides, or, preferably,bromides, in the presence of a basic condensation agent.

The O-alkylation reaction is carried out in polar, aprotic, organicsolvents such as acetone, esters such as ethyl acetate, or ethers,preferably a cyclic ether such as tetrahydrofuran or dioxane.

As basic condensation agents, there may be employed alkali oralkaline-earth metal carbonates such as sodium, potassium, or calciumcarbonates, or tertiary aliphatic amines, such as triethylamine.

O-acylation with (C₂ -C₄)alkanoyl halides may be carried out in anaqueous or non-aqueous reaction medium, for instance aqueous ketonessuch as aqueous acetone, esters such as ethyl acetate, halogenatedhydrocarbons such as methylene chloride, amides such asdimethylformamide, nitriles such as acetonitrile or mixtures of two ormore of the above solvents.

The reaction temperature is comprised between -50° and +50° C.,typically between -20° and +30° C., and preferably the reaction iscarried out in the presence of a proton acceptor which blocks thehydrohalic acid which forms during the reaction.

As proton acceptor agents, there may be cited the tertiary amines, suchas for instance triethylamine, dimethylaniline, or4-dimethylaminopyridine, and the inorganic bases such as sodium,potassium or calcium carbonates.

The acylation may also be carried out using a carboxylic acid as theacylating agent. In this case the reaction is advantageously carried outin the presence of a condensation agent such as a carbodiimide, e.g.DCCI, a carbonyl compound, e.g. carbonyldiimidazole, or an isoxazoliumsalt, e.g. N-ethyl-5-phenyl-isoxazolium perchlorate. O-acylation mayalso be carried out with other functional derivatives such as forinstance activated esters, symmetrical anhydrides or mixed anhydrides.The acylation reactions involving the free acids or their abovementioned functional derivatives are advantageously carried out in ananhydrous reaction medium, for instance in methylene chloride,tetrahydrofuran, dimethylformamide, or acetonitrile. In some particularcases, alternative methods for introducing the G' groups can be easilyenvisaged, said methods being well known in conventional chemistry.

The compounds of formula (I) wherein G' is an alkyl group substitutedwith carboxy may be easily prepared for instance through saponificationof the corresponding esters.

The compounds of formula (I) wherein G is an --OG' group, wherein G' is1-methyl-1-(C₁ -C₄)alkoxycarbonyl-ethyl or 1-ethyl-1-(C₁-C₄)alkoxycarbonyl-ethyl, may be prepared by reaction of thecorresponding compounds (I) wherein G is hydroxy with a compound offormula ##STR14## respectively, in the presence of a base, followed byreaction with thionyl chloride in the (C₁ -C₄)alkanol corresponding tothe desired ester (J.Am.Chem.Soc., 1948, 70, 1153).

The O-alkylation and O-acylation reactions may be carried out directlyon the compounds of formula (I) with a hydroxy group in the tetralinaromatic ring, but in order to avoid N-alkylation or N-acylationside-reactions, the amino group is preferably protected with a temporaryprotecting group R' before submitting the compounds (I) to saidreactions. Suitable protecting groups R' are all the conventional groupswhich may be removed by catalytic hydrogenation or mild acid hydrolysis,such as benzyloxycarbonyl, substituted benzyloxycarbonyl such asmethoxy- or nitro-benzyloxycarbonyl, t-alkoxycarbonyl, such astert-butoxycarbonyl (Boc), or tert-amyloxycarbonyl (Aoc); the Boc groupbeing particularly preferred.

Introduction of the N-protecting R' group, is achieved by reacting thecompounds of formula (I) wherein G is hydroxy with the reactantssuitable for the protection of the amino groups as described forinstance by M. Bodanszky et al., in Peptide Synthesis, 2^(nd) Edition,John Wiley & Sons, 1976, pages 18 and 49, Chapters 3 to 6.

The Boc and Aoc groups for instance may be introduced by reactingdi-tert-butyl- and di-tert-amyl-dicarbonates respectively under basicconditions and in the presence of an organic solvent such as dioxane,tetrahydrofuran, or dimethylformamide.

The benzyloxycarbonyl and substituted benzyloxycarbonyl groups may beintroduced by the general procedure described by E. C. Horning, inOrganic Synthesis, Vol. III, Wiley, New York, 1955, page 167.

The thus obtained compounds of formula (I') ##STR15## wherein E, L andR' are as defined above are then submitted to O-alkylation orO-acylation according to the general, conventional, methods describedabove and then the protecting group R' of the thus obtained compounds offormula (I") ##STR16## wherein E, L, R', and G' are as defined above, isremoved. Removal of the N-protecting groups is achieved by catalytichydrogenation or mild acidic hydrolysis according to well knownliterature methods.

Particularly, the Boc and Aoc groups are removed under acidicconditions, by the action of trifluoroacetic acid. The benzyloxycarbonyland substituted benzyloxycarbonyl groups are cleaved off by catalytichydrogenation preferably using palladium on carbon as the catalyst.

When a compound of formula (I") is obtained wherein G' represents analkyl group substituted with (C₁ -C₄)alkoxycarbonyl, it may besaponified under basic conditions either before or after deprotection ofthe amino group.

The compounds of formula (I) are isolated according to conventionalmethods, preferably as the corresponding addition salts with mineral ororganic acids which suitably allow separation or crystallisation thereofas indicated above, such as picric acid, oxalic acid, or the opticallyactive acids such as mandelic or substituted mandelic acids, orcamphorsulfonic acids, or with the mineral or organic acids which formpharmaceutically acceptable salts such as hydrochloric acid, hydrobromicacid, sulfuric acid, phosphoric acid, methanesulfonic acid,methylsulfuric acid, maleic acid, fumaric acid, and naphthalensulfonicacid.

the free base may be restored by neutralisation and converted intoanother of its acid addition salts or, when G is an --OG' group whereinG' represents an alkyl group substituted with carboxy, it may beconverted into one of its metal salts, typically one of its alkali oralkaline-earth metal salts, such as the sodium or calcium salts.

The compounds of formula (I) which contain only those two asymmetriccarbon atoms which are marked by the asterisks may exist as fourdifferent stereoisomers.

The process of the present invention may be carried out either onracemates or optically pure isomers. In particular, the reactionsinvolved in the above processes do not modify the stereochemistry of thecompounds concerned.

Thus, starting from a compound of formula (IIb) or (IIc), which do notcontain any chiral carbon, or a compound of formula (IId) or (IIa) asthe racemate and a compound of formula (III) as the racemate, a mixtureof the four possible isomers is obtained, i.e. a mixture of the (R,R),(R,S), (S,R), and (S,S) isomers.

Analogously, starting from a compound of formula (III) in optically pureform, a mixture of only two isomers is obtained (e.g. starting from acompound of formula (III) with the (R) absolute configuration, a mixtureof the (R,R) and (S,R) isomers is obtained). If also the compound offormula (IIa) or (IId) is employed in optically pure form, the pureisomers (I) are easily obtained.

When a mixture of four isomers is obtained, it may be resolved into thetwo couples of enantiomers, which are diastereoisomers of each other,i.e. (R,R)+(S,S) and (R,S)+(S,R), by means of known techniques such asfractional crystallisation from a suitable solvent, preferably a loweralkanol, such as ethanol, isopropanol and their mixtures. Each couple oftwo enantiomers may then be separated into the pure isomers typically byformation of diastereoisomeric salts, or by chromatography on chiralcolumns, or by any other suitable technique.

When one of the starting compounds is in optically pure form, the thusobtained mixture of two diastereoisomers is separated into the two pureisomers by the above cited methods.

The starting compounds of formula (II) are known products, or they canbe easily prepared by conventional methods described in the chemicalliterature. As an example, the compounds of formula (IIa) may beprepared by epoxidation of the corresponding styrene derivatives withoxygen in the presence of silver-based catalysts, or by the action ofdimethylsulfonium or dimethylsulfoxonium methylide on the correspondingsubstituted benzaldehyde according to the method described by E. J.Corey in J.Am.Chem.Soc., 1956, 87, 1353.

According to a preferred method of preparation, a compound of formula(IIa) in optically pure form can be obtained by reduction of thecorresponding substituted mandelic acid having the suitably selectedabsolute configuration at the chiral carbon, into the correspondingglycol, esterification of the primary alcohol group with a functionalderivative of a sulfonic acid, such as tosyl chloride or mesyl chloride,and then cyclisation of the thus obtained compound by treatment with astrong base, such as an alkali metal hydroxide, under the conditionsconventionally employed in intramolecular nucleophilic substitutions.

The compounds of formula (IIb) are easily prepared by the action of anoxidizing agent, such as selenium dioxide, on the correspondingacetophenones, in water or in an organic solvent, e.g. a cyclic ether,such as dioxane or tetrahydrofuran.

According to a different method of preparation, said compounds offormula (IIb) are obtained by the action of dimethylsulfoxide on thecorresponding haloacetophenones of formula (IIc) by the method describedby N. Kornblum in J. Am. Chem. Soc., 1957, 79, 6562, or even startingfrom the corresponding dihaloacetophenones by the reaction described byF. Venier in C. R. Acad. Sci., 1968, 266, 1650.

The starting compounds of formula (IIc) are easily prepared byhalogenation of the corresponding ketones or in some instances by aFriedel-Craft reaction using the corresponding substituted benzenederivatives and a haloacetic acid halide.

Finally, the functional derivatives of mandelic or substituted mandelicacids of formula (IId) are prepared from the corresponding acids whichin their turn may be obtained by hydrolysis of mandelonitriles. Theselast compounds may be prepared starting from either substituted orunsubstituted benzaldehyde and hydrogen cyanide or from eitherunsubstituted or substituted benzaldehyde, sodium cyanide and sodiumbisulfite according to well known literature methods. Mandelic acids offormula (IId) obtained as racemates can be easily separated into theoptically pure isomers by forming the diastereoisomeric salts withsuitable optically active bases according to well known methods andprocedures.

The compounds of formula (III) wherein G represents a chlorine atom, ahydroxy group or an --OG' group wherein G' is as defined above, exceptthe compounds of formula (III) wherein G is a 7- or 8-methoxy group, aswell as the optically pure isomers of the compounds of formula (III)wherein G represents hydrogen, chloro, hydroxy or an --OG' group whereinG' has the same meaning as above and their possible salts, are newproducts and represent the key intermediates in the preparation of thecompounds of formula (I). Said compounds of formula (III) representtherefore a further specific object of the present invention.

A preferred group of compounds of formula (III) comprises thosecompounds of formula (III) wherein G represents hydroxy or an --OG'group wherein G' represents (C₁ -C₄)alkyl substituted with carboxy or(C₁ -C₄)alkoxycarbonyl.

The compounds of formula (III) can be prepared starting from a1-tetralone derivative of formula (V) ##STR17## wherein G" representshydrogen, chloro, hydroxy or methoxy, according to a general methodwhich is outlined in Scheme I below: ##STR18##

The sequence of reactions illustrated in Scheme I involves

(i) a Claisen reaction to introduce a 2-formyl group into the1-tetralone derivative (V), through reaction with an alkyl formate inthe presence of sodium,

(ii) reaction of the thus obtained compound of formula (VI) withhydroxylamine under heating in acidic medium,

(iii) opening of the isoxazolidine ring of the compound (VII) andreduction of the 1-oxo group to 1-hydroxy (e.g. by the method describedin Synthesis, 1981, 449),

(iv) dehydration of the obtained intermediate compound with adehydrating system, e.g. POCl₃ /pyridine, and

(v) treatment of the thus obtained compound of formula (VIII) with asuitable reducing agent to afford the corresponding compound of formula(III) wherein G =G" and represents hydrogen, chloro, hydroxy or methoxy.

Reduction of the compounds of formula (VIII) may be carried out in twosteps, e.g. with sodium borohydride first and then with lithium aluminumhydride or isobutylaluminum hydride (DIBAL), or in a single step, e.g.using directly LiAlH₄ or DIBAL. In the former case, the 2-cyano-tetralinoptionally substituted with a G" group may be isolated.

The compounds of formula (III) wherein G is an --OG' group differentfrom methoxy are then prepared by O-alkylation or O-acylation of thecompound (III) wherein G=G"=--OH by the conventional methods describedabove for the O-alkylation and O-acylation of the compounds of formula(I) wherein G is a hydroxy group. Also in this case, the optionalO-alkylation and O-acylation of the compound of formula (III) whereinG=G"=--OH may be carried out preferably with prior protection of theamino group. For prior protection of the amino group there may beemployed not only the N-protecting groups R' listed above for protectionof the --NH-- group of compounds (I) but also 2,2,2-trichloroethyl,benzyl, benzhydryl, and trityl groups either unsubstituted orsubstituted on the benzene ring or on one of the benzene rings withmethoxy or nitro, or it is also possible to form phthalimidoderivatives. Removal of said protecting groups is achieved byconventional techniques, typically by catalytic hydrogenation withpalladium or palladium hydroxide on carbon when 2,2,2-trichloroethyl oroptionally substituted benzyl, benzhydryl, or trityl groups are used andby treatment with hydrazine when phthalimido groups are formed. Trityland methoxytrityl groups can be removed also by mild hydrolysis, e.g. 50% HCOOH.

The compounds of formula (III) wherein G is a hydroxy group may also beprepared starting from a compound of formula (V) wherein G" is a methoxygroup at the same position and submitting the compounds of formula (III)obtained by the general method described in Scheme I to a demethylationreaction with hydrobromic acid.

Also, the compounds of formula (III) wherein G is an --OG' group,wherein G' is ethyl substituted with carboxy or (C₁ -C₄)alkoxycarbonyl,may be prepared starting from the corresponding compounds (III) whereinG is an --OG' group, wherein G' is methyl substituted with carboxy byprotection of the amino group with a Boc or Aoc group, followed by theArndt-Eistert reaction (Ber., 1935, 68, 200) which involves conversionof the acid into the corresponding acyl chloride followed by reaction ofthis last product with diazomethane and hydrolysis in the presence ofAg₂ O.

The 2-cyano-3,4-dihydronaphthalene derivatives of formula (VIII) mayalso be prepared starting from the corresponding 2-tetralones of formula(IX) ##STR19## through reaction with an at least equimolar amount of analkali metal cyanide, typically sodium cyanide, in an aprotic,preferably polar, organic solvent, e.g. dimethylsulfoxyde ordimethylformamide. Said reaction which may be carried out at atemperature comprised between room temperature and the refluxtemperature of the reaction mixture, directly affords the compound offormula (VIII) which is then further processed as described in Scheme I.If desired, the thus obtained racemates of formula (III) may beseparated into their pure isomers by formation of diastereoisomericsalts with optically active organic acids such as camphorsulfonic acids,optionally substituted mandelic acids or other optically active acids.

If the aminomethyltetralin (III) contains a second chiral centre, thediastereoisomers and the four pure isomers can be isolated as describedabove. They can then be employed for the preparation of all the possibleisomers of the compounds of formula (I).

According to another useful method of preparation of the compounds offormula (III), there may be employed as starting compounds thecorresponding carboxylic acids of formula (X) wherein Z is a hydroxygroup ##STR20##

These products are converted into the corresponding amides ((X): Z=NH₂),and the amido group is then transformed into aminomethyl.

The above acids of formula (X) wherein Z is a hydroxy group may beprepared from the corresponding 1-tetralones (V) by a general methodwhich is outlined in Scheme II below: ##STR21## and which involves: (i)a Claisen reaction to introduce a 2-ethoxycarbonyl group in the1-tetralone (V), through reaction with diethylcarbonate in the presenceof sodium,

(ii) reduction of the 1-oxo group of the compound of formula (XI),either catalytically with H₂ in the presence of Pd/C, or chemically withtriethylsilane/trifluoroacetic acid (Tetrahedron, 1967, 23, 2235), orwith triethylsilane/BF_(').sup.· Et₂ O (J.Org.Chem., 1985, 50, 3619) or,again, with triethylsilane/trifluoromethanesulfonic acid (Synthesis,986, 779), and

(iii) saponification of the ester (XII).

Conversion of the acids into the corresponding amides of formula ((X):Z=--NH₂) is carried out by the conventional methods which involvenucleophilic addition of ammonia on the positively polarised carbon ofthe acid functional derivative.

As acid functional derivatives there may be employed acyl chlorides,anhydrides, mixed anhydrides, active esters or suitably activated freeacids, e.g. with DCCI or BOP.

Reduction of the amido group is usefully achieved by way of forinstance, hydride reduction e.g. with lithium aluminum hydride ordiborane, typically borane-methyl sulfide. The reaction is carried outin the presence of an aprotic organic solvent, such as a cyclic orlinear ether, typically dioxane or tetrahydrofuran.

The thus obtained compounds of formula (III) wherein G=G" and representshydrogen, chloro, hydroxy or methoxy, may be converted into the othercompounds of formula (III) as described above.

Starting from the acid of formula ((X): Z --OH), in optically activeform, the compound of formula (III) with the same absolute configurationat the chiral carbon is obtained.

The optically active acids of formula (X) may be obtained starting fromthe corresponding racemates by formation of diastereoisomeric saltsthereof with optically active amines such as d-α-methylbenzylamine,1-α-methylbenzylamine, d-menthylamine, and 1-menthylamine andprecipitation of said salts from a suitably selected solvent.

The acids and the amides of formula (X) in optically pure forms are newcompounds which allow an easy preparation of the optically pure isomers(I) and represent therefore a further specific object of the presentinvention.

The compounds of formula (I) and their salts possess very interestingpharmacological properties as they showed to be active as intestinalmotility modulating agents.

In particular, their effects in reducing colon spontaneous motility havebeen observed in in vitro normalized pharmacological tests and has beenconfirmed in the animal in vivo.

In the in vitro tests, the capability of different concentrations of thephenylethanolaminomethyltetralins of the present invention to reduce,under particular normalised conditions, the spontaneous contractileactivity of isolated proximal colon rat strips has been evaluated.

Not fasted male rats weighing 250-300 g are sacrificed. The proximalpart of the colon, approximately a 2 to 3 cm segment, is removed andsuspended in a 20-ml organ bath containing oxygenated (5% CO₂, 95% O₂)Krebs-Ringer solution with the following mM composition: NaCl 118.4; KCl4.7; CaCl₂ 2.45; MgSO₄ 1.16; NaH₂ PO₄ 3.7; glucose 5.6; NaHCO₃ 30.9,kept at a constant temperature of 37° C. The colon strips submitted to a1 g traction spontaneously contract. The test compounds are addedthereto after stabilisation of the preparation (2h).

The EC₅₀, i.e. the concentration which is effective to reduce by 50% thecontractile activity observed in controls, is determined.

In this test the compounds of the present invention showed a very highactivity characterised, for the most active compounds, by EC₅₀ s in therange of from 1 to 50 nM.

The compounds of formula (I) showed also a surprising specificitytowards the colon. In vitro tests, carried out by the same generalmethod but on isolated rat uterus, showed that a significative effect onspontaneous uterus motility is obtained at doses much higher than thoseactive on colon.

With regard to the compounds described in European Patent EP-B-211,721,the compounds of formula (I) of the present invention showed to be morepotents and more selectives.

As an example, the compound of Example 4(N-[(7-methoxy-1,2,3,4-tetrahydronaphth-2-yl)methyl]-2-hydroxy-2-(3-chlorophenyl)ethanaminehydrochloride) is characterised by an EC₅₀, on colon, of 43 nM and anEC₅₀, on uterus, of 2,453 nM corresponding to a selectivity ratio of 57,whereas the compound described in Example 7 of EP-B-211,721(N-(7-methoxy-1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-2-(3-chlorophenyl)ethanaminehydrochloride) is characterised by an EC₅₀, on colon, of 194 nM and anEC₅₀, on uterus, of 350 nM (selectivity ratio lower than 2).

Also, the compound of Example 10, as the hydrochloride, is characterisedby an EC₅₀, on colon, of 7 nM and an EC₅₀, on uterus, of 50 nM(selectivity ratio of about 7), while the compound described in Example8 of EP-B-211,721, which structurally differs therefrom in the absenceof the --CH₂ -- group between the tetralin moiety and the --NH-- group,is characterised by an EC₅₀ of 110 nM both on colon and uterus(selectivity ratio=1).

In the in vivo tests, intestinal motility in the anesthetized rat by themethod described in EPA-255,415 has been evaluated. The compounds of thepresent invention have shown a very good activity at very low doses.

The phenylethanolaminomethyltetralins of formula (I) and theirpharmaceutically acceptable salts have also a very low toxicity,compatible with the utilization of these products as drugs.

Thus, in another of its embodiments, the present invention concerns thepharmaceutical compositions mainly useful in the treatment of intestinaltroubles comprising, as the active principle, one or more compounds offormula (I) or their pharmaceutically acceptable salts.

In the pharmaceutical compositions of the present invention suitable fororal, sublingual, subcutaneous, intramuscular, intravenous,trans-dermal, or rectal administration, the above active principles maybe administered, in unit dosage forms in admixture with the conventionalpharmaceutical carriers, to mammals for the treatment of intestinalmotility troubles. Suitable unit dosage forms comprise the oral formssuch as tablets, capsules, powders, granules, and the solutions andsuspensions for oral administration, the sublingual and buccal forms,the subcutaneous, intramuscular, intravenous, and rectal forms.

To achieve the desired therapeutical effect, the daily dosage of activeprinciple may vary from 0.01 to 100 mg/kg of body weight. Each unit dosemay contain from 0.1 to 500 mg of active principle in admixture with asuitable pharmaceutical carrier. Said unit dosage form may beadministered from 1 to 4 times a day.

When a solid composition is prepared in tablet form, the main activeingredient is mixed with a pharmaceutical carrier such as gelatine,starch, lactose, magnesium stearate, talc, arabic gum, and the like.Tablets may be coated with sucrose or other suitable materials or theymay be treated so that their activity is extended or delayed and thatthey continually release a predetermined amount of active principle.

A preparation in capsules is obtained by mixing the active ingredientwith a diluent and a lubricant and by filling soft or hard capsules withthe thus obtained mixture.

A liquid preparation in the form of syrup or elixir or for theadministration in drops may contain the active ingredient jointly with apossibly acaloric sweetener, methylparaben, and propylparaben asantiseptics, as well as a flavoring agent and a suitable dye.

Water-dispersible powders or granules may contain the active ingredientmixed with dispersing agents or wetting agents, or suspending agents,such as polyvinylpyrrolidone and the like agents, and with sweetening orflavoring agents.

For rectal administration suppositories are prepared with binding agentsmelting at rectal temperature, for example cocoa butter orpolyethyleneglycols.

For parenteral administration, aqueous suspensions, isotonic salinesolutions or sterile injectable solutions are employed which containpharmacologically compatible dispersing and/or wetting agents, forexample propyleneglycol or butyleneglycol.

The active principle may also be formulated in the form of microcapsulesor microemulsions, possibly with one or more supports or additives.

The main active principle of formula [I) may be administered as the freebase or as a pharmaceutically acceptable salt thereof, as such or as acomplex with, for instance, a dextrine, or even in association orco-administration with other active principles, such as tranquillisers.

The compounds of formula (I) and their salts are also active incontrolling high intraocular pressure, i.e. in normalizing, reducing andmodulating high intraocular pressure. They can therefore be employed inthe treatment of ocular hypertension and glaucoma, an ocular disorderwhich leads to a damage of the optical nerve fibers and may ressort inloss of the visual function, which is characterised, among othersymptoms, by an increase in intraocular pressure.

The high ocular pressure lowering effect of the compounds of formula (I)as well as of their salts may be evaluated in animals, as an example inthe rabbit, by means of a test which involves oral administration oflarge amounts of water, such as that described in Arch. Ophthal., 1969,82,381-384, or in J. Ocul. Pharmacol., 1985, 1(2), 161-168; or rapidi.v. injection of a glucose solution, such as that described in Boll.Ocul., 1979, 58(7-8), 359-66.

The present invention, therefore, also concerns, in still anotherembodiment thereof, an ophthalmic pharmaceutical composition to beadministered topically to the eye, which comprises aphenylethanolaminomethyltetralin of formula (I) or a pharmaceuticallyacceptable salt thereof.

The ophthalmic compositions according to the present invention, assolutions, suspensions, or ointments, may contain from 0.00001 to 1% byweight, more particularly from 0.0001 to 0.2%, of a compound of formula(I) or a pharmaceutically acceptable salt thereof.

Each dosage unit (drop) contains from 10 ng to 1 mg, and preferably from100 ng to 0.2 mg of a phenylethanolaminomethyltetralin. Thesepreparations may be administered by applying, in the eye, 1 or 2 drops,1 to 3 times a day, to provide a daily posology of from 10 ng to 1 mg,and preferably from 100 ng to 0.2 mg, of active principle.

To obtain suitable preparations, the phenylethanolaminomethyltetralinsof the invention may be admixed with a carrier acceptable for a topicalophthalmic administration. As pharmaceutical acceptable carriers for anophthalmic topical administration, there may be cited water, mixtures ofwater and water-miscible solvents, such as lower alkanols, vegetableoils, mineral oils which may contain from 0.5 to 5% by wt. ofhydroxyethylcellulose, ethyl oleate, carboxymethylcellulose,polyvinylpyrrolidone, and other water-soluble polymers, which are nontoxic and compatible with an ophthalmic use, as an example cellulosederivatives, such as methylcellulose, carboxymethylcellulose alkalimetal salts, hydroxymethylcellulose, hydroxyethyl cellulose,hydroxypropylmethylcellulose, acrylates such as polyacrylic acid salts,ethylpolyacrylates, polyacrylamides, natural products such as gelatin,alginates, pectines, tragacanth, karaya gum, chondrus, agar, acacia,starch derivatives, such as starch acetate, hydroxyethyl starch ethers,hydroxypropyl starch, as well as other synthetic derivatives such aspolyvinylalcohol, polyvinylpyrrolidone, polyvinylmethyl ether,polyethylene oxide, neutral carbopol, or xanthan, and their mixtures.The pharmaceutical preparations may also contain non-toxic auxiliarysubstances such as emulsifying, preserving, wetting, bodying agents andthe like such as for instance polyethyleneglycols 200, 300, 400, 600,carbowaxes 1,000, 1,500, 4,000, 6,000, 10,000, antibacterial agents suchas quaternary ammonium compounds, phenylmercuric salts known to havecold sterilising properties and which are non-injurious in use,thimerosal, propylparaben, benzyl alcohol, phenylethanol, bufferingagents, such as alkali metal chlorides, borate, acetate or gluconatebuffers, antioxidants such as sodium metabisulfite, butylatedhydroxyanisole, butylated hydroxytoluene, or the like agents, and otheragents typically used in this field such as sorbitan monolaurate,triethanolamine oleate, polyoxyethylene sorbitan monopalmitate, dioctylalkali metal sulfosuccinate, monothioglycerol, ethylenediaminetetraacetic acid and the like.

Additionally, suitable ophthalmic excipients may be employed such as forinstance phosphate buffer, isotonic boric acid, isotonic alkalinechloride solutions or tromethamine.

The pharmaceutical preparation may also be in the form of a suspensionwherein the soluble particles are water-soluble or insoluble polymers.Such suspensions may contain microparticles or nanoparticles.

The compositions according to the present invention may containadditional active principles. Accordingly, antibiotics, anesthetics,steroid or costicosteroid antiinflammatory agents which are suited forthe treatment of glaucoma, but provoke as a side effect an increase inintraocular pressure, or other high ocular pressure lowering agents, maybe present.

The following examples further illustrate the invention without limitingit. The solvents indicated between parentheses after the melting pointrepresent the crystallisation solvents The rotatory power which isconventionally indicated as [α], should actually read as [α]_(D) ²⁰.

Preparation of the starting compounds of formula (III) Preparation (A)2-aminomethyl-5-methoxy-1,2,3,4-tetrahydronaphthalene hydrochloride

2-cyano-5-methoxy-1,2,3,4-tetrahydro-1-nalphthol is prepared by themethod described in literature for the 6-methoxy compound (Synthesis,1981, 449-451), which is summarized in following steps (i) to (iv), andthen converted into2-aminomethyl-5-methoxy-1,2,3,4-tetrahydronaphthalene hydrochloride bythe method described in details in steps (v) and (vi).

(i) 2-formyl-5-methoxy-3,4-dihydronaphthalen-1(2H)-one

A solution of ethyl formate (20 ml, 0.37 mol) in anhydrous benzene (100ml) is added to sodium ethoxide, prepared from sodium (8.34 g, 0.35 mol)and absolute ethanol, in anhydrous benzene (100 ml). The reactionmixture is cooled to about 0° C. and a solution of5-methoxy-3,4-dihydronaphthalen-1(2H)-one (25 g, 0.14 mol) in anhydrousbenzene (100 ml) is then slowly stirred in. By working up the mixture asdescribed in J. Am. Chem. Soc., 1947, 69, 2942, the above indicatedproduct is recovered (24.8 g); m.p. 68°-70° C.

(ii) 6-methoxy-4,5-dihydronaphth[2,1-d]isoxazole

A mixture of the product obtained in step (i) (23.8 g, 0.11 mol) andhydroxylamine hydrochloride (8.2 g, 0.12 mol) in methanol (300 ml) isrefluxed for ten minutes and then evaporated off under vacuum. Water isadded thereto and the mixture is extracted with ethyl ether affording 19g of the compound indicated in the title; m.p. 84°-86° C.

(iii) 2-cyano-5-methoxy-3,4-dihydronaphthalen-1(2H)-one

The compound obtained in the preceding step (19 g, 0.094 mol) is treatedfor 1 hour, at about 0° C., with sodium methoxide prepared from sodium(4.7 g, 0.188 mol) and anhydrous methanol (250 ml). The reaction mixtureis evaporated under vacuum, water is added thereto and the product isextracted with ethyl acetate yielding 16.7 g of the compound indicatedin the title; m.p. 120°-122° C.

(iv) 2-cyano-5-methoxy-1,2,3,4-tetrahydro-1-naphthol

The compound obtained in step (iii) above (16.2 g, 0.080 mol) is reducedwith sodium borohydride (3.1 g, 0.082 mol) in absolute methanol (500ml). The reaction mixture is concentrated under vacuum, ice-water isadded thereto, the mixture is made acidic by the addition ofconcentrated hydrochloric acid and extracted with ethyl acetate. Uponevaporation of the solvent2-cyano-5-methoxy-1,2,3,4-tetrahydro-1-naphthol (16.2 g) is obtained;m.p. 96°-98° C.

(v) 2-cyano-5-methoxy-3,4-dihydronaphthalene

A mixture of the compound obtained in step (iv) above (16.2 g, 0.079mol) and POCl (30 ml, 0.32 mol) in pyridine (200 ml) is heated for 3hours to 120° C. ext.. The reaction mixture is then cooled and madeacidic by the dropwise addition of 2N HCl. The solution is treated withethyl acetate, the organic phase is recovered, washed with a saturatedsodium bicarbonate solution and then with water. The organic phase isdried over sodium sulfate, filtered and concentrated to dryness yieldingthe compound indicated in the title [9.8 g); m.p. 47°-49° C. (isopropylether).

(vi) 2-aminomethyl-5-methoxy-1,2,3,4-tetrahydronaphthalene hydrochloride

A solution of the compound obtained in step (v) above (9.2 g, 0.05 mol)in anhydrous tetrahydrofuran (150 ml) is added dropwise to a mixture oflithium aluminum hydride (3.8 g, 0.1 mol) and anhydrous tetrahydrofuran(50 ml) under nitrogen atmosphere. The reaction mixture is heated to thereflux temperature for 4 hours, and then cooled. Water (40 ml) is addedthereto and the reaction mixture is extracted with ethyl acetate (2×300ml). The organic phase is dried over sodium sulfate, filtered andconcentrated to dryness. The residue is then purified by flashchromatography eluting with methanol/ammonia 97/3. The hydrochloride isprepared by treating the thus obtained free base with HCl saturatedisopropanol. The product of the title (9 g) is thus obtained;m.p.231°-232° C. (ethanol).

Preparation (B) 2-aminomethyl-6-methoxy-1,2,3,4-tetrahydronaphthalenehydrochloride

The above compound is obtained by following the procedure described inPreparation (A) but starting from 6-methoxy-3,4-dihydronaphthalen-1-oneinstead of 5-methoxy-3,4-di-hydronaphthalen-1-one; m.p. 222°-224° C.(ethanol).

Preparation (C) 2-aminomethyl-8-methoxy-1,2,3,4-tetrahydronaphthalenehydrochloride

Trimethylsylyl cyanide (6.9 g, 9.3 ml, 0.07 mol) is added dropwise in 10minutes to a mixture of 8-methoxy-3,4-di-hydronaphthalen-2(1H)-one (10.9g, 0.06 mol) prepared as described in the literature (J. Chem. Soc.,1958, 409), anhydrous acetonitrile (60 ml) and a catalytic amount ofzinc iodide under nitrogen atmosphere and the obtained mixture is heatedto 80° C. ext. for 3 hours. The reaction mixture is cooled, 1N HCl (20ml) is slowly added thereto and stirring is continued for 2 hours atroom temperature. The solvent is then evaporated off under vacuum, theresidue is taken up in ethyl acetate, and the organic solution is washedwith water, dried over sodium sulfate, filtered and evaporated todryness. The obtained product is triturated with petroleum ether,filtered and dissolved in pyridine (100 ml). POCl₃ (20 ml) is addeddropwise in 10 minutes and the obtained mixture is heated to 120° C.ext. for 3 hours. The reaction mixture is then poured into ice, madeacidic by the addition of concentrated hydrochloric acid and extractedwith ethyl ether. The organic phase is washed with water, dried andevaporated to dryness and the obtained residue is crystallised fromisopropyl ether yielding 2-cyano-8-methoxy-3,4-dihydronaphthalene (7.2g); m.p. 66°-68° C.

The thus obtained product is hydrogenated at room temperature andatmospheric pressure in 95% ethanol (100 ml) using 5% Pd/C as thecatalyst. When the theoretical amount of hydrogen has been consumed, thereaction mixture is filtered, the filtrate is concentrated under reducedpressure, the residue is triturated with petroleum ether and recoveredby filtration affording 2-cyano-8-methoxy-1,2,3,4-tetrahydronaphthalene(7 g); m.p. 66°-68° C.

Said product is dissolved in anhydrous tetrahydrofuran (30 ml) and thethus obtained solution is then added to a suspension of lithium aluminumhydride (1.5 g, 0.04 mol) in anhydrous tetrahydrofuran (20 ml). Thereaction mixture is refluxed for 4 hours, then cooled to roomtemperature and treated with water first and then with ethyl acetate.The organic phase is separated and treated with diluted hydrochloricacid. The acidic aqueous phase is separated, made basic by the additionof ammonia water, and extracted with ethyl acetate. The organic extractis washed with water, dried, and evaporated to dryness. The obtainedresidue is taken up in isopropanol and2-aminomethyl-8-methoxy-1,2,3,4-tetrahydronaphthalene hydrochloride(2.49 g) is then precipitated therefrom by the addition of HCl saturatedisopropanol. M.p. 210°-212° C. (isopropanol).

Preparation (D) 2-aminomethyl-8-hydroxy-1,2,3,4-tetrahydronaphthalenehydrobromide

A mixture of the compound obtained in Preparation (C) above (3 g, 0.013mol) and 48% aqueous HBr (50 ml) is refluxed for 4 hours, and thenevaporated to dryness under vaccum. The obtained residue is taken up inabsolute ethanol (3×50 ml) each time evaporating off the solvent. Theresidue is triturated with acetone, filtered and washed with acetone andthen with ethyl ether thus yielding 2.8 g of the compound of the title.M.p. 233°-235° C. (isopropanol).

Preparation (E) 2-aminomethyl-5-hydroxy-1,2,3,4-tetrahydronaphthalenehydrobromide

The compound of the title is prepared by following the procedure of theforegoing Preparation but starting from the compound of Preparation (B).M.p. 212°-214° C. (ethanol).

Preparation (F) 2(S)-aminomethyl-7-methoxy-1,2,3,4-tetrahydronaphthalenehydrochloride

(i) 7-methoxy-1,2,3,4-tetrahydronaphthalen-2(S)-carboxylic acid

(R)-(+)-α-methylbenzylamine (25.8 ml, 0.2 mol) is added to a solution of7-methoxy-1,2,3,4-tetrahydronaphthalen-2-carboxylic acid racemate (41 g,0.2 mol) in acetone (800 ml) and after 2 hours at room temperature theobtained salt is recovered by filtration (45.2 g) and crystallizedtwelve times from acetone until a product with constant [α] of -20.5°(c=1.4%, CHCl₃) is obtained. This product is then taken up in water (30ml) and the obtained solution is made acidic by the addition ofconcentrated HCl and extracted with ethyl ether. The organic phase isdried and evaporated to dryness and the obtained residue is crystallisedfrom benzene (20 ml) affording 0.9 g of7-methoxy-1,2,3,4-tetrahydronaphthalen-2(S)-carboxylic acid; m.p.133°-135° C.; [α]=-45.1° (c=1.4%, CHCl₃). To determine its absoluteconfiguration, the thus obtained product is converted into thecorresponding 2-amino-7-methoxy-1,2,3,4 -tetrahydronaphthalene by theCurtius reaction.

The [α] of the thus obtained2-amino-7-methoxy-1,2,3,4-tetrahydronaphthalene corresponds to that ofthe 2(S) isomer which is described in EP-A-303,545. As the priorityarrangement of the ligands attached to the asymmetric carbon of2-amino-7-methoxy-1,2,3,4-tetrahydronaphthalene is identical to that of7-methoxy-1,2,3,4-tetrahydronaphthalen-2-carboxylic acid and the Curtiusreaction is stereoconservative, (S) absolute configuration can correctlybe attributed to the thus obtained7-methoxy-1,2,3,4-tetrahydronaphthalen-2-carboxylic acid.

(ii) 7-methoxy-1,2,3,4-tetrahydronaphthalen-2(S)-carboxamide

A solution of triethylamine (10.2 ml, 0.072 mol) in acetone (50 ml) isadded in 15 minutes to a solution of the acid obtained in step (i) (10.8g, 0.052 mol) in acetone (200 ml) cooled to -10° C. A solution of ethylchloroformate (7.9 ml, 0.080 mol) in acetone (80 ml is then addedthereto and after 1.5 hours at -10° C., concentrated ammonia water (16.6ml, 0.133 mol) is dripped in. The reaction mixture is then kept at -10°C. for 1 hour and at room temperature for 3 hours. Acetone is evaporatedoff, the residue is taken up in ethyl acetate (500 ml) and the obtainedsolution is washed sequentially with water, a sodium bicarbonatesolution, 6N hydrochloric acid, and water. Then it is dried andevaporated to dryness. The residue is triturated in isopropyl ether andfiltered yielding the amide of the title (9.5 g), m.p. 159°-161° C.(ethyl acetate); [α]=-52.2° (c=1.4%, CHCl₃). Enantiomeric excess: 96.5%,

(iii) 2(S)-aminomethyl-7-methoxy-1,2,3,4-tetrahydronaphthalenehydrochloride

A solution of the compound obtained in step (ii) above (9.5 g, 0.046mol) in anhydrous tetrahydrofuran (167 ml) is heated to the refluxtemperature under nitrogen atmosphere and 10M borane-dimethylsulfide(14.2 ml, 0.142 mol) in anhydrous tetrahydrofuran (60 ml) is thendripped in. The reaction mixture is refluxed for 4 hours and then cooledto 0°-5° C. Methanol (95 ml) is slowly added thereto, the solution isrefluxed for 1 hour and then evaporated to dryness. The residue is takenup in 1N sodium hydroxide and the obtained solution is then extractedwith ethyl acetate. The organic phase is washed with water, dried andevaporated to dryness The obtained residue is purified by flashchromatography eluting with a mixture methanol/ammonia 98/2. The thusobtained product is dissolved in isopropanol (30 ml) and hydrogenchloride saturated isopropanol is then added thereto to precipitate thecompound of the title (5.3 g); m.p. 228°-230° C.; [α]=-80.4° (c=1.4%,MeOH).

The starting 7-methoxy-1,2,3,4-tetrahydronaphthalen-2-carboxylic acid,which is a known product, can be prepared as follows: a solution of7-methoxy-3,4-dihydronaphthalene-1(2H)-one (66.4 g, 0.376 mol) inanhydrous tetrahydrofuran (350 ml) is added in 1 hour to a mixture ofdistilled diethylcarbonate (116 ml, 0.957 mol), 80% sodium hydride (39.7g, 1.32 mol) and anhydrous tetrahydrofuran (350 ml) heated to 60° C. Thethus obtained reaction mixture is refluxed for 4 hours and then cooled.Acetic acid is then added dropwise up to acidic pH and water is addeduntil complete dissolution of the precipitate occurs. The solution isextracted with ethyl ether, the organic phase is washed with water andwith a sodium bicarbonate solution, dried and evaporated to dryness. Thethus obtained oily product is purified by distillation under reducedpressure yielding 90 g of7-methoxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-carboxylic acid ethylester. B.p.₀.4 mmHg 160°-165° C.

The thus obtained product is dissolved in a mixture of glacial aceticacid (600 ml) and 70% perchloric acid (4 ml) and is hydrogenated at roomtemperature and atmospheric pressure for 3 hours using 10% Pd/C as thehydrogenation catalyst. The mixture is then filtered on celite, thefiltrate is poured into water (4500 ml) and extracted with ethylacetate. The organic phase is washed with water and then with a sodiumbicarbonate saturated solution, then it is dried over sodium sulfate,filtered and concentrated to dryness yielding an oily product which isdistilled at 0.3 mmHg and 130° C.

7-methoxy-1,2,3,4-tetrahydronaphthalen-2-carboxylic acid ethyl ester(65.8 g) is thus obtained.

A mixture of the thus obtained ester (159.5 g, 0.68 mol) and sodiumhydroxide (29.9 g, 0.75 mol) in water (600 ml) and 95% ethanol (600 ml)is refluxed for 2 and 1/2 hours. Ethanol is evaporated off, the solutionis made acidic by the addition of concentrated hydrochloric acid andextracted with ethyl acetate. The organic extract is dried over sodiumsulfate, filtered and evaporated to dryness thus yielding7-methoxy-1,2,3,4-tetrahydronaphthalen-2-carboxylic acid which is thencrystallised from isopropyl ether. M.p. 125°-127° C.

Alternatively, compound (F) may also be obtained starting from theracemate by the following method:

(i') A solution of L (+)-mandelic acid (11.93 g, 0.078 mol) in methanol(100 ml) is added to a solution of2-aminomethyl-7-methoxy-1,2,3,4-tetrahydronaphthalene (15 g, 0.078 mol)in methanol (100 ml).

The precipitate is separated from the mother liquors by filtration andit is recrystallised seven times from methanol thus affording a compoundcharacterised by [α]=-31.4° (c=1.4%, MeOH).

(ii') The salt is taken up in 0.1 N HCl, and the obtained solution isthen extracted with ethyl acetate. The aqueous phase is made basic bythe addition of a sodium carbonate solution and extracted with ethylacetate. This last organic extract is then dried and evaporated todryness to afford a residue which is dissolved in isopropanol. Thecompound of the title is then precipitated therefrom by the addition ofhydrogen chloride saturated isopropanol and is recovered by filtrationM.p. 228°-230° C.; [α]=-79.0° (c=1.4%, MeOH).

Preparation (G) 2(R)-aminomethyl-7-methoxy-1,2,3,4-tetrahydronaphthalenehydrochloride

(i) 7-methoxy-1,2,3,4-tetrahydronaphthalen-2(R)-carboxylic acid

The mother liquors from salt precipitation as well as first and secondcrystallisations described in Preparation (F)(i) are combined andevaporated to dryness. Hydrochloric acid is added to the residue and thesolution is extracted with ethyl ether. The organic phase is evaporatedto dryness, affording7-methoxy-1,2,3,4-tetrahydronaphthalen-2-carboxylic acid (26 g, 0.126mol). Said acid is dissolved in acetone (250 ml) and(S)-(-)-α-methylbenzylamine (16.3 ml, 0.126 mol) is added to the thusobtained solution. After 2 hours at room temperature the mixture isfiltered and the precipitated salt is recovered (33.5 g). Said salt iscrystallised ten times from acetone then it is taken up in water (30ml), the aqueous solution is made acidic by the addition of concentratedhydrochloric acid and extract-ed with ethyl ether. The organic phase isdried, filtered and evaporated to dryness affording7-methoxy-1,2,3,4-tetrahydronaphthalen-2(R)-carboxylic acid (1 g). M.p.133°-135° C. (benzene); [α]=+44.6° (c 32 1.4%, CHC₃).

The above acid is then converted into2-amino-7-methoxy-1,2,3,4-tetrahydronaphthalene hydrochloride by themethod described in Preparation (F)(i). A product is obtained which ischaracterised by [α]=+66.6° (c=0.5%, MeOH) that corresponds to the [α]value of 2(R)-amino-7-methoxy-1,2,3,4-tetrahydronaphthalene (MolecularPharmacology, 1982, 22, 281). The absolute configuration of the abovecompound is thus confirmed.

(ii) 7-methoxy-1,2,3,4-tetrahydronaphthalen-2(R)-carboxamide

This compound (9.5 g) is obtained following the procedure described inPreparation (F)(ii) but starting from7-methoxy-1,2,3,4-tetrahydronaphthalen-2(R)-carboxylic acid (10.8 g,0.052 mol). M.p. 157°-159° C. (ethyl acetate); [α]=+52.7° (c=1.4%,CHC₃). Enantiomeric excess: 94%.

(iii) 2(R)-aminomethyl-7-methoxy-1,2,3,4-tetrahydronaphthalenehydrochloride

Following the same procedure of Preparation (F)(iii) but starting from7-methoxy-1,2,3,4-tetrahydronaphthalen-2(R)carboxamide (9 g, 0.044 mol),the compound of the title (5.5 g) is obtained; m.p. 229°-231° C.(isopropanol); [α]=+83.6° C. (c=1.4%, MeOH).

Alternatively, compound (G) may also be obtained starting from themother liquors of salt precipitation as well as first and secondcrystallisation described in alternative Preparation (F)(i') accordingto the following method: the methanol solution is evaporated to dryness,the residue is taken up in 1N hydrochloric acid and the obtainedsolution is washed with ethyl acetate. The aqueous solution is madebasic by the addition of 1N NaOH and extracted with ethyl acetate. Theorganic phase is dried and concentrated to dryness, the thus obtainedresidue is dissolved in methanol and an equimolar amount ofD(-)-mandelic acid is added thereto. The precipitate which forms isrecovered by filtration and crystallised from methanol seven times thusaffording a product with [α]=+31.8° (c=1.4%, MeOH).

The thus obtained salt is dissolved in 0.1N hydrochloric acid and thesolution is extracted with ethyl acetate. The aqueous solution is thenmade basic by the addition of aqueous Na₂ CO₃ and extracted with ethylacetate. The organic phase is dried and evaporated to dryness. Theresidue is dissolved in isopropanol and HCl saturated isopropanol isthen added thereto to precipitate compound (G). M.p. 228°-230° C.;[α]=+83.1° (c=1.4%, MeOH).

Preparation (H) 2(R)-aminomethyl-7-hydroxy-1,2,3,4-tetrahydronaphthalene

A solution of the compound obtained in Preparation (G) (5 g, 0.022 mol)in 48% aqueous hydrobromic acid (100 ml) is refluxed for 5 hours, andthen it is evaporated to dryness. The residue is taken up inconcentrated ammoniun hydroxide (30 ml), the solution is extracted withethyl acetate (4×200 ml) and the organic extracts are combined, dried,filtered and concentrated to dryness. Crystallisation of the residuefrom isopropanol (80 ml) affords the compound indicated in the title(2.4 g). M.p. 192°-194° C.; [α]=+116.78° (c=1%, MeOH).

Preparation (I) 2(S)-aminomethyl-7-hydroxy-1,2,3,4-tetrahydronaphthalene

The above compound (2.9 g) is obtained by following the procedure ofPreparation (H) but starting from the compound obtained in Preparation(F) (5 g, 0.022 mol); m.p. 191°-193° C. (isopropanol); [α]=-106.5°(c=1%, MeOH).

Preparation (J) 2-aminomethyl-6-hydroxy-1,2,3,4-tetrahydronaphthalene

The above compound is obtained by following the procedure of Preparation(H) but starting from the compound obtain in Preparation (B). M.p.181°-183° C. (isopropanol).

Preparation (K) Ethyl[(2-aminomethyl-1,2,3,4-tetrahydronaphth-7-yl)oxy]acetate hydrochloride

(i)7-hydroxy-2-(N-tertbutoxycarbonyl)aminomethyl-1,2,3,4-tetrahydronaphthalene

2-aminomethyl-7-methoxy-1,2,3,4-tetrahydronaphthalene is obtained by theprocess described in Preparation (A), but starting from7-methoxy-3,4-dihydronaphthalen-1-one, and is treated with aqueoushydrobromic acid according to the procedure described in Preparation(H). A suspension of the thus obtained2-aminomethyl-7-hydroxy-1,2,3,4-tetrahydronaphthalene (6 g, 0.034 mol)in dimethylformamide (89 ml) and triethylamine (4.7 ml, 0.034 mol) isstirred at room temperature for 10 minutes and 90%di-tert-butyl-dicarbonate (8.2 g, 0.034 mol) is then added thereto. Thereaction mixture is stirred at room temperature for 3 hours and thenpoured into water (about 400 ml) and the obtained solution is extractedwith ethyl acetate. The organic phase is washed with water, dried oversodium sulfate, filtered and evaporated to dryness affording an oilyproduct which is purified by flash chromatography eluting with a mixtureethyl acetate/cyclohexane 2/8.

The residual oil is pumped to dryness under reduced pressure thusyielding a vitreous solid. IR (KBr):3364 (b): O--H, CON--H; 1690: ═OCONH cm⁻¹.

(ii) Ethyl[(2-(N-tertbutoxycarbonyl)aminomethyl-1,2,3,4-tetrahydronaphth-7-yl)oxy]acetateA mixture of the above product (3.4 g, 0.009 mol), powdered potassiumcarbonate (4 g, 0.09 mol) and acetone (100 ml) is stirred at roomtemperature for 30 minutes and then ethyl bromoacetate (4.56 g, 3 ml,0.027 mol) is added thereto. The reaction mixture is refluxed for 5hours, filtered and concentrated under vacuum. The residue is dissolvedin ethyl ether, the solution is washed with water, dried over sodiumsulfate and evaporated to dryness under reduced pressure. The obtainedproduct is triturated with isopropyl ether and filtered thus affordingethyl [(2-(N-tertbutoxy-carbonyl)aminomethyl-1,2,3,4-tetrahydronaphth-7-yl)oxy]acetate (m.p.94°-97° C.).

(iii) Ethyl [(2-aminomethyl-1,2,3,4-tetrahydronaphth-7-yl)oxy]acetatehydrochloride

A mixture of the product obtained in step (ii) above (2.1 g, 0.0058 mol)and absolute ethanol (15 ml) is cooled to about 0° C. and 7.2N hydrogenchloride in ethanol (5 ml) is then added thereto. When the addition isterminated, the reaction mixture is heated to about 50° Cfor 30 minutesand then concentrated to dryness under vacuum. The obtained residue istriturated with acetone and filtered yielding 1.2 g of the compound ofthe title; m.p. 136°-138° C. (isopropanol).

Preparation (L) Ethyl[(2-aminomethyl-1,2,3,4-tetrahydronaphth-7-yl)oxy]butanoatehydrochloride

A mixture of the compound obtained in Preparation (K)(i) (3.8 g, 0.013mol), powdered potassium carbonate (4 g, 0.09 mol) and acetone (100 ml)is stirred at room temperature for 30 minutes and then ethyl4-bromobutanoate (11.5 g, 0.06 mol) is added thereto. The reactionmixture is refluxed for 10 hours, filtered and concentrated undervacuum. The residue is dissolved in a mixture of absolute ethanol (15ml) and 6N hydrogen chloride in absolute ethanol (25 ml). The reactionmixture is heated to about 90° C. ext. for 4 hours and then it isconcentrated to dryness under vacuum. The obtained residue is trituratedwith acetone and filtered yielding 2.7 g of the compound of the title;m.p. 146°-148° C.

Preparation (M) 2-aminomethyl-7-hydroxy-1,2,3,4-tetrahydronaphthalene

Starting from 2-aminomethyl-7-methoxy-1,2,3,4-tetrahydronaphthaleneracemate (prepared as described in EP-A-213080) and following theprocedure described in Preparation (H),2-aminomethyl-7-hydroxy-1,2,3,4-tetrahydronaphthalene is obtained; m.p.187°-189° C. (isopropanol).

Preparation (N) 2-aminomethyl-1,2,3,4-tetrahydronaphthalenehydrochloride

The compound indicated in the title is obtained by following theprocedure described in Preparation (C) but starting from3,4-dihydronaphthalen-2(1H)-one; m.p. 228°-230° C. (ethanol).

Preparation (O) (+)2-aminomethyl-6-methoxy-1,2,3,4-tetrahydronaphthalene hydrochloride[(2R) or (2S)-aminomethyl-6-methoxy-1,2,3,4-tetrahydronaphthalenehydrochloride]

(i) (+) 6-methoxy-1,2,3,4-tetrahydronaphthalen-2-carboxylic acid [(2R)or (2S) 6-methoxy-1,2,3,4-tetrahydronaphthalen-2-carboxylic acid]

A solution of (R)-(+)-α-methylbenzylamine (88.3 g, 93 ml, 0.72 mol) inacetone (500 ml) is added to a solution of6-methoxy-1,2,3,4-tetrahydronaphthalen-2-carboxylic acid racemate (150g, 0.727 mol) in acetone (250 ml). The reaction mixture is allowed tostand at room temperature overnight, then the salt is recovered byfiltration, and it is crystallised eleven times from acetone thusobtaining a compound (6.3 g) characterised by [α]=+47.7° (c=1.4%,CHCl₃).

The thus obtained salt is taken up in 0.1 N NaOH and the aqueoussolution is washed with ethyl ether (3×30 ml) before being treated withdecolorizing carbon. The reaction mixture is then filtered, and thesolution is made acidic by the addition of concentrated hydrochloricacid. The thus obtained acid is recovered by filtration, washed withwater and with ethyl ether, and dried in the oven, thus affording 3.3 gof optically active acid. M.p. 129°-30° C.; [α]=+47.9° (c=1.4%, CHCl₃).

(ii) (+) 6-methoxy-1,2,3,4,-tetrahydronaphthalen-2-carboxamide [(2R) or(2S) 6-methoxy-1,2,3,4-tetrahydronaphthalen-2-carboxamide]

A solution of triethylamine (2.7 ml, 0.019 mol) and ethyl chloroformate(2 ml, 0.021 mol) in acetone (40 ml) is added to a solution of the acidobtained in step (i) (3 g, 0.014 mol) in acetone (50 ml) cooled to -10°C. After 1,5 hours at -10° C., concentrated NH₄ OH (4.5 ml, 0.036 mol)is added dropwise and the reaction mixture is allowed to stand at -10°C. for 1 hour and at room temperature overnight. The solution isconcentrated under vacuum, ethyl acetate (150 ml) is added to theobtained residue and the solution is washed sequentially with water, asaturated sodium bicarbonate solution, 6N hydrochloric acid, and water,then it is dried and concentrated to dryness. The residue is trituratedwith isopropyl ether and filtered thus affording 1.7 g of the aboveindicated amide; m.p. 136°-138° C.; [α]=+40.2° (c= 1.4%, CHCl₃).

(iii) (+) 2-aminomethyl-6-methoxy-1,2,3,4-tetrahydronaphthalenehydrochloride [(2R) or(2S)-aminomethyl-6-methoxy-1,2,3,4-tetrahydronaphthalene hydrochloride]

A solution of the compound of step (ii) (1.6 g, 0.0077 mol) in anhydroustetrahydrofuran (20 ml) is refluxed under nitrogen atmosphere and a 10Msolution of borane-methyl sulfide (2.3 ml, 0.023 mol) and anhydroustetrahydrofuran (5 ml) are gradually dripped in. The reaction mixture isheated to the reflux temperature for 4 hours, methanol (5 ml) is slowlyadded thereto and the mixture is refluxed for one further hour. 1N HCl(10 ml) is added and the obtained mixture is refluxed for 1 hour andthen concentrated under reduced pressure and made basic by the additionof ammonium hydroxide. The aqueous solution is extracted with ethylacetate, the organic phase is washed with water, dried and evaporated.The residue is purified by flash chromatography eluting with a mixtureof methanol/ammonia 98/2. The thus obtained product is dissolved inisopropanol (30 ml), the solution is filtered and HCl saturatedisopropanol is added thereto. The precipitate is recovered by filtration(1.1 g); m.p. 245°-255° C.; [α]=+70.7° (c=1.4%, MeOH).

Alternatively, Compound (O) may also be prepared starting from theracemate by to the following method:

(i') A solution of L(+)-mandelic acid (11.93 g, 0.078 mol) in methanol(100 ml) is added to a solution of2-aminomethyl-6-methoxy-1,2,3,4-tetrahydronaphthalene (15 g, 0.078 mol)in methanol (100 ml). The precipitate is separated from the motherliquors by filtration and crystallised seven times from methanolaffording a compound characterised by [α]=+92.7° (c=1.4 %, MeOH).

(ii') The thus obtained salt is taken up in 0.1 N HCl, and the solutionis extracted with ethyl acetate. The aqueous solution is made basic bythe addition of a sodium carbonate solution and extracted with ethylacetate which is then evaporated off. The residue is dissolved inisopropanol and hydrogen chloride saturated isopropanol is then addedthereto. Compound (O) is then recovered by filtration. [α]=+76.7° (c=1.4%, MeOH).

Preparation (P) (+)2-aminomethyl-6-hydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide [(2R)or (2S)-aminomethyl-6-hydroxy-1,2,3,4-tetrahydronaphthalenehydrobromide]

A mixture of the compound of Preparation (O) above (0.86 g, 0.0038 mol)and aqueous 48% hydrobromic acid (15 ml) is heated to the refluxtemperature for 5 hours. The solvent is evaporated off to dryness andthe residue is taken up in absolute ethanol (3×15 ml) evaporating offthe solvent each time. The residue is triturated with acetone andfiltered affording the compound indicated in the title (0.82 g). M.p.248°-252° C.; [α]=+61° (c=1.4%, MeOH).

Preparation (Q) (-)2-aminomethyl-6-methoxy-1,2,3,4-tetrahydronaphthalene hydrochloride[(2S) or (2R)-aminomethyl-6-methoxy-1,2,3,4-tetrahydronaphthalenehydrochloride]

(i) (-) 6-methoxy-1,2,3,4,-tetrahydronaphthalen-2-carboxylic acid [(2S)or (2R) 6-methoxy-1,2,3,4-tetrahydronaphthalen-2-carboxylic acid]

The mother liquors from salt precipitation, first, second, and thirdcrystallisation described in Preparation (O)(i) are combined andevaporated to dryness. Hydrochloric acid is added to the obtainedresidue, and the solution is extracted with ethyl ether. The organicextract is then evaporated to dryness affording6-methoxy-1,2,3,4-tetrahydronaphthalen-2-carboxylic acid (126 g, 0.61mol). Said acid is dissolved in acetone (2000 ml) and a solution of(S)-(-)-α-methylbenzylamine (80.6 ml, 0.61 mol) in acetone (500 ml) isthen added thereto. The precipitated salt (116 g) is recovered byfiltration and crystallised ten times from acetone affording 5.6 g of acompound with [α]=-46.7° (c=1.4%, CHCl₃).

The residue is taken up in 0.1 NaOH, and the obtained solution is washedwith ethyl ether (3×30 ml), and made acidic by the addition ofconcentrated HCl. The obtained acid is recovered by filtration, washedwith water, and with petroleum ether and dried in the oven, yielding3.37 g of the optically active acid. M.p. 129°-130° C.; [α]=-52.5°(c=1.4%, CHCl₃).

(ii) (-) 6-methoxy-1,2,3,4,-tetrahydronaphthalen-2-carboxamide [(2S) or(2R) 6-methoxy-1,2,3,4-tetrahydronaphthalen-2-carboxamide]

The above indicated amide (1.7 g) is obtained, using the same procedureas in Preparation (O)(ii) but starting from the compound obtained instep (i) above (3 g, 0.014 mol); m.p. 138°-140° C.; [α]=-45.8° (c=1.4 %,CHCl₃).

(iii) (-) 2-aminomethyl-6-methoxy-1,2,3,4-tetrahydronaphthalenehydrochloride [(2S) or(2R)-aminomethyl-6-methoxy-1,2,3,4-tetrahydronaphthalene hydrochloride]

The compound indicated in the title (1 g) is obtained by following theprocedure described in Preparation (O)(iii) but starting from (-)6-methoxy-1,2,3,4-tetrahydronaphthalen-2-carboxamide (1.61 g, 0.0078mol); m.p. 258°-260° C. (dec.); [α]=-73.8° (c=1.4%, MeOH).

Alternatively Compound (Q) may be prepared starting from the motherliquors of salt precipitation, first and second crystallisation ofalternative Preparation (O)(i') by the following method : the methanolsolution is evaporated off to dryness and the residue is taken up in 1NHCl. The obtained solution is washed with ethyl acetate, made basic bythe addition of lN NaOH and extracted with ethyl acetate. The organicextract is concentrated to dryness, the residue is dissolved in methanoland the equimolar amount of D(-)-mandelic acid is then added thereto.The precipitate is recovered by filtration and crystallised from MeOHseven times affording a product with [α]=-90.5° (c=1.4%, MeOH). The thusobtained salt is then dissolved in 0.1N HCl and the solution is washedwith ethyl acetate, made basic by the addition of aqueous sodiumcarbonate, and extracted with ethyl acetate. The organic phase is dried,filtered and evaporated to dryness. The residue is dissolved inisopropanol and HCl saturated isopropanol is added thereto Compound (Q)is recovered by filtration. [α]=-76.4° (c=1.4%, MeOH)

Preparation (R) (-)2-aminomethyl-6-hydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide [(2S)or (2R)-aminomethyl-6-hydroxy-1,2,3,4-tetrahydronaphthalenehydrobromide]

The above compound is obtained by following the procedure described inPreparation (P) but starting from the compound of Preparation (Q) (0.75g, 0.0033 mol). M.p. 250°-252° C.; [α]=-64.2° (c=1.4%, MeOH).

Preparation (S) Ethyl[(2(R)-aminomethyl-1,2,3,4-tetrahydronalphth-7-yl)oxy]acetatehydrochloride

(i) 2(R)-(N-tertbutoxycarbonyl)aminomethyl-1,2,3,4-tetrahydronaphthalene

A suspension of the Compound obtained in Preparation (H) as the freebase (4.6 g, 0.026 mol) in dimethylformamide (60 ml) and triethylamine(3.6 ml, 0.026 mol) is stirred for 15 minutes at room temperature andthen 90 % di-tertbutyl-di-carbonate (6.3 g, 0.026 mol) is added thereto.After stirring for 3 hours at room temperature, the reaction mixture ispoured into water (about 300 ml) and extracted with ethyl acetate. Theorganic phase is washed with water, dried and evaporated to dryness. Theresidue is purified by flash chromatography eluting with ethylacetate/cyclohexane 2/8.

(ii) Ethyl[(2(R)-(N-tertbutoxycarbonyl)aminomethyl-1,2,3,4-tetrahydronaphth-7-yl)oxy]acetate

A mixture of the above product (3.6 g, 0.013 mol), and powderedpotassium carbonate (4,4 g, 0.03 mol) in acetone (100 ml) is stirred atroom temperature for 1 hour and then ethyl bromoacetate (5.1 g, 0.03mol) is added thereto. The reaction mixture is refluxed for 5 hours,filtered and concentrated under reduced pressure. The residue isdissolved in ethyl ether, the organic solution is washed with water,dried and evaporated to dryness under reduced pressure. The obtainedresidue is washed with a small amount of isopropyl ether affording ethyl[(2R) 2-(N-tertbutoxycarbonyl)aminomethyl-1,2,3,4-tetrahydronaphth-7-yl)oxy]acetate (2.3 g).

(iii) Ethyl [((2R)2-aminomethyl-1,2,3,4-tetrahydronaphth-7-yl)oxy]acetate hydrochloride

A 7.2N solution of hydrogen chloride in ethanol (5 ml) is added to asolution of the compound obtained in step (ii) above (2.3 g, 0.0063 mol)in absolute ethanol (15 ml) and the obtained mixture is heated to 50° C.for 30 minutes, and then concentrated under reduced pressure. Theresidue is washed with a small amount of acetone affording the compoundindicated in the title (1.4 g).

Preparation (T) Ethyl[(2(S)-aminomethyl-1,2,3,4-tetrahydronaphth-7-Yl)oxy]acetatehydrochloride

(i) 2(S)-(N-tertbutoxycarbonyl)aminomethyl-1,2,3,4-tetrahydronaphthalene

The above product (2.2 g) is obtained by following the proceduredescribed in Preparation (S)(i) but starting from the Compound ofPreparation (I) (2.1 g, 0.012 mol).

(ii) Ethyl[(2(S)-(N-tertbutoxycarbonyl)aminomethyl-1,2,3,4-tetrahydronaphth-7-yl)oxy]acetate

The above compound (1.4 g) is obtained by following the proceduredescribed in Preaparation (S)(ii) but starting from the compoundobtained in step (i) above (2.2 g, 0.008 mol).

(iii) Ethyl [((2S)2-aminomethyl-1,2,3,4-tetrahydronaphth-7-yl)oxy]acetate hydrochloride

The compound indicated in the title (0.8 g) is obtained starting fromthe product of step (ii) above and following the procedure ofPreparation (S)(iii).

Preparation (U) Ethyl [((2S)2-aminomethyl-1,2,3,4-tetrahydronaphth-6yl)-oxy]acetate hydrochlorideand Preparation (V) Ethyl [((2R)2-aminomethyl-1,2,3,4-tetrahydronaphth-6-yl)-oxy]acetate hydrochloride

The compounds indicated above are obtained in yields of from 15 to 20%,by following the procedure described in Preparation (S), steps (i),(ii), and (iii), but starting from the compounds of Preparation (P) and(R).

In the case of the 6-substituted derivatives, assignement of the (R)absolute configuration to the dextrorotatory enantiomer and of the (S)absolute configuration to the levorotatory isomer, even if likely, hasnot been confirmed.

As a matter of fact, unlike the 7-substituted derivatives, whereabsolute configuration has been easily attributed to the starting parentcompound (see Preparation (F)(i)) by comparison with known compounds,within the series of 6-substituted derivatives, this method cannot beemployed as the optically active compounds which, by analogy, should beused as reference compounds, are not described in the literature.

EXAMPLE 1N-[(2(R)-7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)methyl]-(2R)-2-hydroxy-2-(3-chlorophenyl)ethanaminehydrochloride

(i)N-[(2(R)-7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)methyl]-(R)-3-chloromandelamide

A suspension of the product of Preparation (H) above (2.2 g, 0.013 mol),(R)-3-chloromandelic acid (2.3 g, 0.013 mol),benzotriazolyl-N-oxytris-(dimethylamino)phosphonium hexafluorophosphate(BOP)(5.2 g, 0.013 mol) in anhydrous methylene chloride (100 ml) andtriethylamine (1.8 ml, 1.3 g, 0.013 mol) is stirred at room temperaturefor 5 hours. Saline (50 ml) is then added thereto and the mixture isstirred for further 30 minutes. The organic phase is separated, washedsequentially with 2N HCl (2×30 ml), water, saturated sodium bicarbonate,and water. Then it is dried and evaporated to dryness. The obtainedproduct is purified by flash chromatography eluting with a mixture ethylacetate/cyclohexane 1/1. The thus obtained oily product is dried underreduced pressure at 40° C. for 2 days yielding the above indicated amideas a vitreous powder; [α]=+31.6° (c=1%, MeOH).

(ii)N-[(2(R)-7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)methyl]-(2R)-2-hydroxy-2-(3-chlorophenyl)ethanaminehydrochloride

A solution of the compound obtained in step (i) above (2.7 g, 0.008 mol)in anhydrous tetrahydrofuran (50 ml) is heated to the reflux temperatureunder nitrogen atmosphere and a 10M solution of borane-methyl sulfide(2.4 ml, 0.024 mol) in anhydrous tetrahydrofuran (20 ml) is slowlydripped in. The thus obtained reaction mixture is refluxed for 4 hours,then it is cooled and methanol (20 ml) is added thereto dropwise. Themixture is refluxed for 30 minutes and concentrated to dryness and theproduct, obtained as the free base, is purified by flash chromatographyeluting with methanol. The obtained base is dissolved in acetone (40 ml)and the solution is made acidic by the addition of hydrochloric acidsaturated isopropanol, thus affording the compound indicated in thetitle (1 g) which is then dried under reduced pressure, at 40° C., for 2days. M.p. 145°-148° C.; [α]=+34° (c=1%, MeOH).

EXAMPLE 2N-[(2(S)-7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)methyl]-(2R)-2-hydroxy-2-(3-chlorophenyl)ethanamine

(i)N-[(2(S)-7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)methyl]-(R)-3-chloromandelamide

The above amide (4 g) is obtained as a vitreous powder, by following theprocedure of Example 1 step (i) but starting from a mixture of theproduct of Preparation (I) (3.0 g, 0.017 mol), (R)-3-chloromandelic acid3.2 g, 0.017 mol), BOP (6.8 g, 0.017 mol) and triethylamine (2.4 ml,0.017 mol) in anhydrous methylene chloride (120 ml); [α]=-80.6° (c=1%,MeOH).

(ii)N-[(2(S)-7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)methyl]-(2R)-2-hydroxy-2-(3-chlorophenyl)ethanamine

By following the procedure of Example 1 step (ii), but starting from theabove amide (3.6 g, 0.010 mol), the desired product is obtained as thefree base. The obtained compound is then purified by flashchromatography eluting with a mixture methanol/ethyl acetate 60/40 andthen by crystallisation from methanol. Yield 1.9 g. M.p. 159°-161 ° C.;[α]=-77.2° (c=0.5%, MeOH).

EXAMPLE 3N-[(8-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)methyl]-2-hydroxy-2-(3-chloroohenyl)ethanaminehydrochloride

(i)N-[(8-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)methyl]-3-chloromandelamide

A mixture of the compound obtained in Preparation (D) (2.2 g, 0.0085mol), 3-chloromandelic acid (1.6 g, 0.0085 mol), BOP (3.4 g, 0.0085mol), and triethylamine (2.4 ml, 1.72 g, 0.017 mol) in methylenechloride (50 ml) is stirred at room temperature for 5 hours. The mixtureis then diluted with ethyl acetate, washed sequentially with water,diluted hydrochloric acid, saturated aqueous sodium bicarbonate, andwater, dried and evaporated to dryness. The above amide (1.6 g) is thenobtained with an IR absorption spectrum that corresponds to the assignedstructure. IR (KBr) : 3342 (d) : O-H, CON-H; 1641 : HNC=O cm⁻¹.

(ii)N-[(8-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)methyl]-2-hydroxy-2-(3-chlorophenyl)ethanaminehydrochloride

A solution of the product of step (i) above (1.6 g, 0.0046 mol) inanhydrous tetrahydrofuran (30 ml) is heated to the reflux temperatureunder nitrogen atmosphere and a mixture of a 10M solution ofborane-methyl sulfide (1.4 ml, 0.0014 mol) and anhydrous tetrahydrofuran(10 ml) is slowly dripped in. The obtained solution is refluxed for 4hours and then diluted with methanol (10 ml). The solvent is evaporatedoff under vacuum and the obtained residue is dissolved in ethyl ether.The organic solution is made acidic by the addition of HCl saturatedisopropanol and the product of the title is obtained therefrom byfiltration (0.9 g) M.p. 175°-178° C.

EXAMPLES 4 to 9

By using the general procedure described in the foregoing Examples 1 to3, but starting from 3-chloromandelic acid and the suitably selected1,2,3,4-tetrahydronaphthalene derivatives, the following compounds offormula (I) are obtained via the intermediate compounds of formula (IV)indicated between parentheses and characterised by the reported IRabsorption maxima.

EXAMPLE 4N-[(7-methoxy-1,2,3,4-tetrahydronaphth-2-yl)methyl]-2-hydroxy-2-(3-chlorophenyl)ethanaminehydrochloride

M.p. 170°-173° C. (isopropanol].

[N-[(7-methoxy-1,2,3,4-tetrahydronaphth-2-yl)methyl]-3-chloromandelamide]

IR (neat): 3390 (sh), 3324: O--H, CON--H; 1655: NHC═O cm⁻¹.

EXAMPLE 5N-[(6-methoxy-1,2,3,4-tetrahydronaphth-2-yl)methyl]-2-hydroxy-2-(3-chlorophenyl)ethanaminehydrochloride

M.p. 205°-208° C. (absolute ethanol).

[N-[(6-methoxy-1,2,3,4-tetrahydronaphth-2-yl)methyl]-3-chloromandelamide].

IR (KBr): 3520 (sh), 3300 (sh), 3247: O--H, CON--H; 1627, 1650: NHC═Ocm⁻¹.

EXAMPLE 6N-[(6-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)methyl]-2-hydroxy-2-(3-chlorophenyl)ethanaminehydrochloride

M.p. 174°-176° C. (isopropanol).

[N-[(6-hydroxy-1,2,3,4-tetrahydronaphth-2-yl-)methyl]-3-chloromandelamide].

IR (KBr): 3349 (b): O--H, CON--H; 1659: NHC═O cm⁻¹.

EXAMPLE 7N-[(5-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)methyl]-2-hydroxy-2-(3-chlorophenyl)ethanaminehydrochloride

M.p. 177°-180° C. (triturated in acetone).

[N-[(5-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)methyl]-3-chloromandelamide].

IR (KBr): 3365 (b): O--H, CON--H; 1659: NHC═O cm⁻¹.

EXAMPLE 8N-[(8-methoxy-1,2,3,4-tetrahydronaphth-2-yl)methyl]-2-hydroxy-2-(3-chlorophenyl)ethanaminehydrochloride

M.p. 186°-188° C. (isopropanol).

[N-[(8-methoxy-1,2,3,4-tetrahydronaphth-2-yl)methyl]-3-chloromandelamide].

IR (KBr): 3319 (d): O--H, CON--H; 1658: NHC═O cm⁻¹.

EXAMPLE 9N-[(5-methoxy-1,2,3,4-tetrahydronaphth-2-yl)methyl]-2-hydroxy-2-(3-chlorophenyl)ethanaminehydrochloride

M.p. 216°-218° C. (95% ethanol).

[N-[(5-methoxy-1,2,3,4-tetrahydronaphth-2-yl)methyl]-3-chloromandelamide;m.p. 92°-95° C.].

EXAMPLE 10N-[(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)methyl]-2-hydroxy-2-(3-chlorophenyl)ethanamineoxalate

This compound is prepared by following the procedure described inExample 1 steps (i) and (ii), but starting from the compound ofPreparation (M) and treating the product obtained as the free base witha solution of oxalic acid in acetone. M.p. 218°-220° C. (triturated inacetone).

EXAMPLE 11 Ethyl[[2-[N-[2-(3-chlorophenyl)-2-hydroxy]ethyl]aminomethyl-1,2,3,4-tetrahydronaphth-7-yl]oxy]acetatehydrochloride

A mixture of the product of Preparation (K), as the free base (2.8 g,0.010 mol) and 3-chlorostyrene oxide (2.6 g, 0.015 mol) in anhydrousdimethyl sulfoxide (15 ml) is heated to 80° C. for 8 hours understirring The reaction mixture is poured into water and the solution isextracted with ethyl acetate. The organic phase is separated, washedwith water, dried over sodium sulfate, filtered and evaporated todryness. The residue is dissolved in hot isopropanol (40 ml) and HClsaturated isopropanol is then added thereto. The compound indicated inthe title is recovered by filtration affording 1.4 g of a product withm.p. 157°-161° C.

EXAMPLE 12 Ethyl4[[2-[N-[2-(3-chlorophenyl)-2-hydroxy]ethyl]aminomethyl-1,2,3,4-tetrahydronaphth-7-yl]oxy]butanoatehydrochloride

The compound indicated in the title is obtained by using the sameprocedure as in Example 11 but starting from the compound of Preparation(L). M.p. 138°-145° C. (isopropanol).

EXAMPLE 13N-[(7-methoxy-1,2,3,4-tetrahydronaphth-2-yl)methyl]-2-hydroxy-2-(3,4-dichlorophenyl)ethanaminehydrochloride

(i)N-[(7-methoxy-1,2,3,4-tetrahydronaphth-2-yl)methyl]3,4-dichloromandelamide

By following the procedure of Example 1(i) but starting from3,4-dichloromandelic acid (3.1 g, 0.014 mol) and2-aminomethyl-7-methoxy-1,2,3,4-tetrahydronaphthalene (2.67 g, 0.014mol), N-[(7-methoxy-1,2,3,4-tetrahydronaphth-2-yl)methyl]-3,4-dichloromandelamide (4.5 g) is obtained as an oily productcharacterised by the following IR absorption maxima 3380 (b): O--H,CON--H; and 1641: NHC═0 cm⁻¹.

(ii)N-[(7-methoxy-1,2,3,4-tetrahydronaphth-2-yl)-methyl]-2-hydroxy-2-(3,4-dichlorophenyl)ethanaminehydrochloride.

A solution of the product obtained in above step (i) (4.5 g, 0.0114 mol)in tetrahydrofuran (75 ml) is heated to the reflux temperature undernitrogen atmosphere and a mixture of a 10M solution of borane-methylsulfide (3.5 ml, 0.035 mol) and tetrahydrofuran (10 ml) is slowly addedthereto. The resulting solution is refluxed for 4 hours then methanol(25 ml) is slowly dripped in The solution is concentrated under reducedpressure, the residue is dissolved in isopropanol and precipitatedtherefrom by the addition of HCl in isopropanol. The obtained product iscrystallised from ethanol affording 1.87 g of the compound of the title.M.p. 194°-198° C.

EXAMPLE 14 Ethyl[[2-[N-(2-phenyl)-2-hydroxy]ethyl]aminomethyl-1,2,3,4-tetrahydronaphth-7-yl]oxy]acetatehydrochloride

The compound of the title is obtained by using the procedure of Example11 but replacing 3-chlorostyrene oxide with styrene oxide. M.p.163°-170° C. (isopropanol).

EXAMPLE 15N-[(7-methoxy-1,2,3,4-tetrahydronaphth-2-yl)methyl]-2-hydroxy-2-phenylethanaminehydrochloride

A mixture of styrene oxide (1 g, 0.0083 mol), 2-aminomethyl-7-methoxy-1,2,3,4-tetrahydronalphthalene (1.5 g, 0.0078 mol) indimethylsulfoxide (20 ml) is heated to 80° C. ext. for 10 hours. Thereaction mixture is then poured into water and the solution is extractedwith ethyl acetate. The organic phase is separated, washed with water,dried and evaporated to dryness The obtained oily residue is purified byflash chromatography eluting with a mixture methylene chloride/methanol95/5. The combined fractions are evaporated off, the obtained residue isdissolved in ethyl ether and HCl saturated isopropanol is then addedthereto. The precipitate is filtered yielding 0.5 g of the compound ofthe title. M.p. 187°-192° C.

EXAMPLE 16N-[(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)methyl]-2-hydroxy-2-phenylethanaminehydrochloride

By following the procedure of Example 15 but replacing2-aminomethyl-7-methoxy-1,2,3,4-tetrahydronalohthalene with the compoundof Preparation (M) a product is obtained which is washed with a smallamount of acetone thus affording the compound of the title with m.p.155°-158° C.

EXAMPLE 17N-[(1,2,3,4-tetrahydronaphth-2-yl)-methyl]-2-hydroxy-2-(3-chloro)ohenylethanaminehydrochloride

A mixture of 2-amino-1,2,3,4-tetrahydronaphthalene free base (1.4 g,0.0087 mol) obtained by neutralisation of the correspondinghydrochloride (Preparation (N)) with sodium hydroxide and extractionwith ethyl acetate, and 3-chlorostyrene oxide (2 g, 0.013 mol) indimethylsulfoxide (15 ml) is heated to 80° C. ext. for 8 hours. Thereaction mixture is then poured into water (about 100 ml) and thesolution is extracted with ethyl ether. The organic phase is washed withwater, dried and evaporated to dryness. The residue is taken up inpetroleum ether and filtered. The obtained product (1.5 g) is dissolvedin acetone (50 ml) under gentle heating and HCl saturated isopropanol isadded thereto. The precipitate which forms is recovered by filtrationaffording 1.5 g of the compound of the title; m.p. 232°-235° C.

EXAMPLE 18[[2-[N-(2-(3-chlorophenyl)-2-hydroxy]ethyl]aminomethyl-1,2,3,4-tetrahydronaphth-7-yl]oxy]aceticacid

A mixture of the compound of Example 11, as free base, (2.0 g, 0.0047mol) and potassium hydroxide (0.3 g, 0.0057 mol), in 95% ethanol (30 ml)and water (30 ml) is heated to 50° C. for 5 hours, then ethanol isevaporated off and water (20 ml) is added. The aqueous solution isextracted with ethyl ether (2×50 ml). The organic phase is treated withcarbon, and filtered and 1N HCl is then added thereto up to pH 6.5. Theprecipitate which forms is recovered by filtration affording thecompound of the title with m.p. 213°-217° C.

EXAMPLE 19 N-[((2R) or (2S) 6-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)methyl]-(2R)-2-hydroxy-2-(3-chlorophenyl)ethanamine hydrochloride

(i) N-[(2R) or (2S)6-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)methyl]-(R)-3-chloromandelamide

A mixture of the compound of Preparation (P) (0.6 g, 0.0023 mol),(R)-3-chloromandelic acid (0.4 g, 0.0023 mol), BOP (1 g, 0.0023 mol) andtriethylamine (1.8 ml, 1.3 g, 0.013 mol) in methylene chloride (20 ml),is stirred at room temperature overnight. Ethyl acetate (60 ml) is thenadded thereto and the mixture is washed sequentially with 2N HCl, asaturated sodium bicarbonate solution, and water. The organic phase isseparated, dried and concentrated to dryness. The residue is purified bychromatography eluting with a mixture ethyl acetate/cyclohexane 1/1,thus affording 0.7 g of the above indicated amide. [α]=+21.9° (c=1%,MeOH).

(ii) N-[((2R) or (2S)6-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)methyl]-(2R)-2-hydroxy-2-(3-chlorophenyl)ethanaminehydrochloride

A 10M solution of borane-methyl sulfide (0.5 ml, 0.005 mol) in anhydroustetrahydrofuran (5 ml) is slowly added to a solution of the compoundobtained in above step (i) (0.5 g, 0.0014 mol) in anhydroustetrahydrofuran (20 ml) heated to the reflux temperature under nitrogenatmosphere. The thus obtained reaction mixture is refluxed for 4 hours,then methanol (5 ml) is slowly dripped in and 30 minutes later 1N HCl (4ml) is added thereto. The mixture is refluxed for 30 minutes,concentrated under vacuum, made basic by the addition of ammoniumhydroxide, and extracted with ethyl acetate. The organic phase is washedwith water, dried and evaporated to dryness. The obtained residue isdissolved in hot isopropanol (10 ml), the solution is made acidic by theaddition of HCl saturated isopropanol, and the precipitate which formsis recovered by filtration (0.24 g). M.p. 175°-177° C.; [α]=+18.3°(c=1%, MeOH).

EXAMPLE 20 N-[((2S) or (2R) 6-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)methyl]-(2R)-2-hydroxy-2-(3-chlorophenyl)ethanamine hydrochloride

(i) N-[(2S) or (2R)6-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)methyl]-(R)-3-chloromandelamide

The above amide (0.6 g) is obtained by following the procedure ofExample 19 (i) but starting from the compound of Preparation (R) (0.5 g,0.002 mol), (R)-3-chlormandelic acid (0.4 g, 0.002 mol), BOP (0.88 g,0.002 mol) and triethylamine (0.6 ml, 0.4 g, 0.004 mol) in methylenechloride (20 ml). [α]=-75.1° (c=1%, MeOH).

(ii) N-[((2S) or (2R)6-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)methyl]-(2R)-2-hydroxy-2-(3-chlorophenyl)ethanaminehydrochloride

The compound indicated in the title (0.34 g) is obtained by followingthe procedure described in Example 19 (ii) but starting from the amideobtained in step (i) above (0.5 g, 0.0014 mol). M.p. 217°-219° C.[α]=-72.2° (c=1%, MeOH).

EXAMPLE 21N-[(6-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)methyl]-2-hydroxy-2-(4-chlorophenyl)ethanamine

(i)N-[(6-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)methyl]-4-chloromandelamide

A mixture of the hydrobromide of the compound obtained in Preparation(J) (3.77 g, 0.015 mol), 4-chloromandelic acid (2.8 g, 0.015 mol), BOP(6.3 g, 0.015 mol) and triethylamine (3 g, 0.03 mol) in methylenechloride (80 ml) is stirred at room temperature overnight. Ethyl acetateis then added thereto, and the mixture is washed sequentially withwater, 2N HCl, a saturated sodium bicarbonate solution and water. Thesolution is dried and concentrated under reduced pressure affording anoily product which is purified by chromatography eluting with a mixtureethyl acetate/cyclohexane 1/1 thus yielding 3.47 g of the aboveindicated amide.

(ii)N-[(6-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)methyl]-2-hydroxy-2-(4-chlorophenyl)ethanamine

A solution of the compound obtained in step (i) above (3.2 g, 0.0092mol) in anhydrous tetrahydrofuran (65 ml) is heated to the refluxtemperature under nitrogen atmosphere and a 10M solution ofborane-methyl sulfide (2.8 ml, 0.028 mol) and anhydrous tetrahydrofuran(10 ml) are then added thereto. The mixture is refluxed for 4 hours,methanol (30 ml) is slowly added thereto and refluxing is prolonged foran additional hour. lN HCl (60 ml) is then added thereto and the mixtureis refluxed for 1 hour, and concentrated under reduced pressure. Theresidue is taken up in ethyl acetate, the organic solution is washedwith ammonium hydroxide and then with water, dried over sodium sulfate,filtered and concentrated to dryness under reduced pressure affording asolid which is washed with isopropyl ether (2.3 g). M.p. 150°-153° C.

EXAMPLE 22N-[(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)methyl]-2-hydroxy-2-(2-chlorophenyl)ethanaminefumarate

(i)N-[(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)methyl]-2-chloromandelamide

The above amide (2.2 g) is prepared by following the procedure ofExample 19 (i) but starting from the compound of Preparation (M) (1.5 g,0.0085 mol), 2-chloromandelic acid (1.6 g, 0.0055 mol), BOP (3.75 g,0.0085 mol) and triethylamine (0.86 g, 0.0085 mol) in methylene chloride(55 ml).

(ii)N-[(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)methyl]-2-hydroxy-2-(2-chlorophenyl)ethanaminefumarate

The compound of the title (0.09 g) is prepared by following theprocedure of Example 19 (ii) but starting from the compound obtained instep (i) above (1.9 g, 0.0055 mol) and using fumaric acid in isopropanolinstead of HCl saturated isopropanol. M.p. 215°-217° C.

EXAMPLE 23N-[(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)methyl]-2-hydroxy-2-(4-chlorophenyl)ethanaminehemifumarate

(i)N-(7-hydroxy-1,2,3,4-tetrahyironaphth-2-yl)methyl]-4-chloromandelamide

The above amide (2.2 g) is prepared by following the procedure ofExample 19 (i) but starting from the compound of Preparation (M) (2 g,0.0113 mol), 4-chloromandelic acid (2.1 g, 0.0113 mol), BOP (5 g, 0.0113mol) and triethylamine (1.6 ml, 0.0113 mol) in methylene chloride

(ii)N-[(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)methyl]-2-hydroxy-2-(4-chlorophenyl)ethanaminehemifumarate

The compound of the title (0.18 g) is prepared by following theprocedure of Example 19 (ii) but starting from the amide obtained instep (i) above (2 g, 0.0058 mol) and using fumaric acid in isopropanolinstead of HCl saturated isopropanol. M.p. 210°-213° C.

EXAMPLE 24N-[(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)methyl]-2-hydroxy-2-(3-methoxyphenyl)ethanaminehydrochloride

(i) 3-methoxystyrene oxide

A mixture of 3-methoxybenzaldehyde (13.4 g, 0.098 mol), a solution ofsodium hydroxide (200 g) in water (200 ml), dodecyl-dimethylsulfoniummethyl sulfate (51 g, 0.15 mol) and toluene (150 ml) is stirred for 17hours. Ice is then added and the organic phase is separated, washed withwater (3×50 ml), dried over sodium sulfate, filtered and concentratedunder reduced pressure. The above product is recovered from the thusobtained residue by distillation at 135°-140° C. and 30 mmHg.

(ii)N-[(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)methyl]-2-hydroxy-2-(3-methoxyphenyl)ethanaminehydrochloride

A mixture of the above product, which has a titre of 71.5%, asdetermined by chromatography, (1.2 g, 0.0059 mol) and of the compound ofPreparation (M) (1.4 g, 0.0079 mol) in absolute ethanol (60 ml) isrefluxed overnight, then it is concentrated under reduced pressure. Theoily residue is purified by chromatography eluting with ethyl acetate.The obtained product is dissolved in ethyl ether and HCl saturatedisopropanol is then added thereto to precipitate the compound of thetitle (0.36 g).

EXAMPLE 25N-[(6-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)methyl]-2-hydroxy-2-(3-methoxyphenyl)ethanaminehydrochloride

The compound of the title (0.62 g) is obtained by following theprocedure of Example 24 (ii) but starting from the compound ofPreparation (J) (1.9 g) instead of the compound of Preparation (M).

EXAMPLE 26 N-[(2(R)7-methoxy-1,2,3,4-tetrahydronaphth-2-yl)methyl]-(2R)-2-hydroxy-2-(3-chlorophenyl)ethanaminehydrochloride

A mixture of 2(R)-aminomethyl-7-methoxy-1,2,3,4-tetrahydronaphthalenehydrochloride (0.11 g, 0.48 mmol) (Preparation (G)), (R)-3-chlorostyreneoxide (0.07 g, 0.46 mmol), and triethylamine (0.13 ml, 0.96 mmol) indimethylsulfoxide (5 ml) is heated to 60° C. ext. for 48 hours. Thereaction mixture is then poured into water and the aqueous solution isextracted with ethyl acetate. The organic extract is washed with water,dried over sodium sulfate, filtered and concentrated to dryness.

The obtained residue is purified by flash chromatography eluting withmethylene chloride.

The obtained product is dissolved in acetone and the compound of thetitle (0.02 g) is then precipitated therefrom by the addition of HClsaturated isopropanol and recovered by filtration. M.p. 214-216° C.[α]=+25.1° (c=1%, MeOH).

EXAMPLE 27 N-[(2(S)7-methoxy-1,2,3,4-tetrahydronaphth-2-yl)methyl]-(2R)-2-hydroxy-2-(3-chlorophenyl)ethanaminehydrochloride

The compound of the title (0.02 g) is prepared by following the sameprocedure as in Example 26 but starting from2(S)-aminomethyl-7-methoxy-1,2,3,4-tetrahydronaphthalene hydrochloride(0.11 g, 0.48 mmol), (R)-3-chlorostyrene oxide (0.07 g, 0.46 mmol) andtriethylamine (0.13 ml, 0.96 mmol) in dimethylsulfoxide (5 ml). M.p.189°-191° C.; [α]=-70.7° (c =1%, MeOH).

EXAMPLE 28 N-[(2R) or (2S) 6-methoxy-1,2,3,4-tetrahydronaphth-2-yl)methyl]-(2R)-2-hydroxy-2-(3-chlorophenyl)ethanamine hydrochloride

The compound of the title (0.5 g) is prepared by following the sameprocedure as in Example 26 but starting from (2R) (or (2S))2-aminomethyl-6-methoxy-1,2,3,4-tetrahydronaph-thalene (0.63 g, 0.0033mol) obtained by neutralisation of the corresponding hydrochloridedescribed in Preparation (O), and (R)-3-chlorostyrene oxide (0.6 g,0.0039 mol) in dimethylsulfoxide (10 ml).

EXAMPLE 29 N-[((2S) or (2R)6-methoxy-1,2,3,4-tetrahydronaphth-2-vl)-methyl]-(2R)-2-hydroxy-2-(3-chlorophenyl)ethanaminehydrochloride

The compound of the title (0.4 g) is prepared by following the sameprocedure as in Example 26 but starting from (2S) (or (2R))2-aminomethyl-6-methoxy-1,2,3,4-tetrahydronaphth alene (0.5 g, 0.0026mol) obtained by neutralisation of the corresponding hydrochloridedescribed in Preparation (Q), and (R)-3-chlorostyrene oxide (0.6 g,0.0039 mol) in dimethylsulfoxide (10 ml).

EXAMPLE 30 Ethyl[[2(R)-[N-(2-(3-chlorophenyl)-2(R)-hydroxy]ethyl]aminomethyl-1,2,3,4-tetrahydronaphth-7-yl]oxy]acetate hydrochloride

A mixture of ethyl[[2(R)-aminomethyl-1,2,3,4-tetrahydronaphth-7-yl]oxy]acetate (1 g,0.0038 mol) obtained by neutralisation of the correspondinghydrochloride described in Preparation (S), and (R)-3-chlorostyreneoxide (0.8 g, 0.0052 mol) in anhydrous dimethylsulfoxide (15 ml) isheated to 80° C. ext. under stirring for 10 hours, then it is pouredinto water and the solution is extracted with ethyl acetate. The organicextract is washed with water, dried over sodium sulfate, filtered andevaporated to dryness. The residue is dissolved in hot isopropanol andthe compound of the title is then precipitated from the obtainedsolution by the addition of HCl saturated isopropanol (0.6 g).

EXAMPLE 31 Ethyl[[2(S)-[N-(2-(3-chlorophenyl)-2(R)-hydroxy]ethyl]aminomethyl-1,2,3,4-tetrahydronaphth-7-yl]oxy]acetatehydrochloride

The compound indicated in the title (0.5 g) is obtained by using thesame procedure as in Example 30 but starting from ethyl[[2(S)-aminomethyl-1,2,3,4-tetrahydronaphth-7-yl]oxy]acetate (1 g,0.0038 mol) obtained by neutralisation of the correspondinghydrochloride described in Preparation (T), instead of the (R)enantiomer.

EXAMPLE 32 Ethyl [[2(R) (or2(S))-[N-(2-(3-chlorophenyl)-2(R)-hydroxy]ethyl]aminomethyl-1,2,3,4-tetrahydronaphth-6-yl]oxy]acetatehydrochloride

The compound indicated in the title (1.2 g) is obtained by using thesame procedure as in Example 30 but starting from a mixture of ethyl[[2(R) (or 2(S))-aminomethyl-1,2,3,4-tetrahydronaphth-6-yl]oxy]acetate(2.2 g, 0.0083 mol) obtained by neutralisation of the correspondinghydrochloride described in Preparation (U), and (R)-3-chlorostyreneoxide (1.8 g, 0.012 mol) in anhydrous dimethylsulfoxide (20 ml).

EXAMPLE 33 Ethyl [[2(S) (or2(R))™[N-(2-(3-chlorophenyl)-2(R)-hydroxy]ethyl]aminomethyl-1,2,3,4-tetrahyironaphth-6-yl-]oxy]acetatehydrochloride

The compound indicated in the title (1.1 g) is obtained by using thesame procedure as in Example 30 but starting from a mxture of ethyl[[2(S) (or 2(R))-aminomethyl-1,2,3,4-tetranydronaphth-6-yl]oxy]acetate(1.8 g, 0.0068 mol) obtained by neutralisation of the correspondinghydrochloride described in Preparation (V), and (R)-3-chlorostyreneoxide (1.5 g, 0.0097 mol) in anhydrous dimethylsulfoxide (20 ml).

EXAMPLE 34

Tablets containing the compound of Example 6 as the active ingredientand having the following composition

    ______________________________________                                        Compound of Example 6   20 mg                                                 Microcristalline cellulose                                                                            30 mg                                                 Dried corn starch       30 mg                                                 Lactose                 100 mg                                                Magnesium stearate      5 mg                                                  ______________________________________                                    

are prepared by grinding the active ingredient up to a particle size of0.4 mm, sifting the obtained powder by a 0.4 mm sieve, mixing all theabove ingredients together and compressing the obtained mixture intablets.

Analogously, tablets containing 40 mg of active ingredient each can beprepared.

EXAMPLE 35

By operating as described in Example 34 but using the compound ofExample 7 as the active ingredient, tablets of the following compositioncan be prepared:

    ______________________________________                                        Compound of Example 7  50.0 mg                                                Dried corn starch      100.0 mg                                               Lactose                95.0 mg                                                Talc                   4.5 mg                                                 Magnesium stearate     0.5 mg                                                 ______________________________________                                    

EXAMPLE 36

10,000 capsules, each containing 50 mg of active principle are preparedstarting from the following ingredients Compound of Example 4 (500 g),microcrystalline cellulose (495 g), amorphous silica gel (5 g). Theabove ingredients are admixed together and filled into hard gelatincapsules of size 4.

EXAMPLE 37

An aqueous sterile solution suitable for the preparation of vials forparenteral administration, containing the compound of Example 6 as theactive ingredient is prepared with the following composition

    ______________________________________                                        Compound of Example 6 30       mg                                             Sodium chloride       5        mg                                             Distilled water       q.s. to 2                                                                              ml                                             ______________________________________                                    

EXAMPLE 38

An ophthalmic solution is prepared by mixing the following ingredientsaccording to conventional techniques

    ______________________________________                                        Compound of Example 4                                                                              1.0         mg                                           NaH.sub.2 PO.sub.4   10.4        mg                                           Na.sub.2 HPO.sub.4   2.4         mg                                           Chlorobutanol        5.0         mg                                           Hydroxypropylmethylcellulose                                                                       5.0         mg                                           1N NaOH              q.s. to pH = 7.4                                         Distilled water      q.s. to 1.0 ml                                           ______________________________________                                    

We claim:
 1. A phenylethanolaminomethyltetraline of formula (I)##STR22## wherein E represents hydrogen, (C₁ -C₄)alkyl, (C₁ -C₄)alkoxy,phenyl, nitro, halogen, or trifluoromethyl,L represents hydrogen, (C₁-C₄)alkyl, (C₁ -C₄)alkoxy, phenyl, nitro, or halogen, or E and L takentogether represent a group --CH═CH--CH═CH-- or --CH₂ --CH₂ --CH₂ --CH₂--, and G represents hydrogen, chloro, hydroxy or an --OG' group whereinG' represents a (C₁ -C₄)alkyl group either unsubstituted or substitutedwith hydroxy, (C₁ -C₄)alkoxy, (C₁ -C₄)alkoxycarbonyl, carboxy, or (C₃-C₇)cycloalkyl; a (C₃ -C₇)cycloalkyl group; or a (C₂ -C₄)alkanoyl group;and salts thereof.
 2. A compound of claim 1 wherein G representshydrogen, hydroxy or a group --OG' wherein G' represents unsubstitutedor substituted (C₁ -C₄)alkyl.
 3. A compound of claim 2 wherein Grepresents hydrogen, hydroxy or a group --OG' wherein G' represents (C₁-C₄)alkyl unsubstituted or substituted with carbo(C₁ -C₄)alkoxy orcarboxy.
 4. A compound as in any of claims 1 to 3 wherein the chiralcarbon atom in the ethanolamino chain has absolute configuration (R). 5.A pharmaceutical composition containing one or more compounds of claim 1as the main active ingredient.
 6. The pharmaceutical composition ofclaim 5 for systemic administration in unit dosage form containing from0.1 to 500 mg of active principle.
 7. The pharmaceutical composition ofclaim 5 containing from 10 ng to 1 mg of active principle per unitdosage form.